Pyridine anchors for HMG-CoA reductase inhibitors

ABSTRACT

Compounds which are useful as inhibitors of cholesterol biosynthesis and thus as hypocholesterolemic agents are provided which have a quinoline or a pyridine anchor attached by means of a linker to a binding domain sidechain, which compounds inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of application Ser. No. 07/588,800 filed Sep. 27,1990, abandoned, which is a continuation-in-part of U.S. patentapplication Ser. No. 485,398 (filed Feb. 26, 1990), abandoned, which isa continuation-in-part of U.S. patent application Ser. No. 272,610(filed Nov. 17, 1988), abandoned, which is a continuation-in-part ofU.S. patent application Ser. No. 237,349 (filed Aug. 29, 1988),abandoned.

FIELD OF THE INVENTION

The present invention is related to compounds and pharmaceuticalcompositions useful as hypocholesterolemic and hypolipidemic agents.More particularly, this invention concerns (1) certain inhibitors of theenzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAreductase) that contain a quinoline or pyridine nucleus attached bymeans of a linker to an HMG-binding domain sidechain, (2) pharmaceuticalcompositions containing such compounds and (3) a method of loweringblood serum cholesterol levels employing such pharmaceuticalcompositions.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with the present invention, there are provided certainquinoline- and pyridine-containing compounds that are potent inhibitorsof cholesterol biosynthesis by virtue of their ability to inhibit theenzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoAreductase).

In particular, in its broadest chemical compound aspect, the presentinvention provides compounds of the formula ##STR1## wherein: Am is abinding domain sidechain;

X is a linker;

R¹ and R² are the same or different and are each independently selectedfrom

(i) hydrogen,

(ii) alkyl,

(iii) aryl,

(iv) cycloalkyl,

(v) aralkyl,

(vi) aralkoxy,

(vii) alkenyl,

(viii) cycloalkenyl, and

(ix) heterocyclo (e.g., thienyl, benzodioxolyl);

R³ is selected from

(i) hydrogen,

(ii) lower alkyl,

(iii) aryl,

(iv) cycloalkyl,

(v) alkoxy,

(vi) aralkyl,

(vii) aralkoxy,

(viii) alkenyl,

(ix) cycloalkenyl,

(x) halo-substituted alkyl,

(xi) adamantyl, and

(xii) heterocyclo (e.g., thienyl, benzodioxolyl);

R⁴ is selected from

(i) hydrogen,

(ii) lower alkyl,

(iii) aryl,

(iv) cycloalkyl,

(v) alkoxy,

(vi) aralkyl,

(vii) aralkoxy,

(viii) alkenyl,

(ix) cycloalkenyl,

(x) adamantyl,

(xi) halogen,

(xii) halo-substituted alkyl (e.g., trifluoromethyl), and

(xiii) heterocyclo (e.g., thienyl, benzodioxolyl);

or R³ and R⁴ taken together can be --(CH₂)p--, ##STR2## or (CH═CH)₂ ;but when A_(m) is ##STR3## or a δ lactone thereof, R³ and R⁴ cannot be(CH═CH)₂ ;

R⁶ is hydrogen or lower alkyl;

R⁸ is hydrogen, lower alkyl, alkali metal, or alkaline earth metal;

n is 0 or 1;

p is 3, 4 or 5;

q is 0, 1, 2, or 3; and

r is 0, 1, 2, or 3.

In another aspect, the present invention provides pharmaceuticalcompositions, useful as hypolipidemic or hypocholesterolemic agentscomprising a hypolipidemic or hypocholesterolemic amount of a compoundin accordance with this invention as set forth above, in combinationwith a pharmaceutically acceptable carrier.

In another aspect, the present invention provides a method of inhibitingcholesterol biosynthesis in a patient in need of such treatment byadministering a pharmaceutical composition in accordance with thepresent invention as defined above.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided compoundsuseful in inhibiting the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A(HMG-CoA reductase), which inhibitors are useful as hypocholesterolemicand hypolipidemic agents, and which compounds comprise a quinolinenucleus or pyridine nucleus ##STR4## linked by a suitable linker (X) toan HMG-binding domain sidechain (Am) (R¹ -R⁴ and n are as definedabove).

The quinoline and pyridine nuclei appear to act as hydrophobic anchorsof the inhibitor, by binding to a hydrophobic pocket of the reductaseenzyme, which results in enhanced inhibitory activity relative tocompounds without such an anchor.

Preferred Moieties

In preferred embodiments of the invention, (Am) is an HMG-binding domainsidechain having a dihydroxy or a phosphinic acid function.

A suitable phosphinic (or phosphonic when X is CH₂ --O--) acidHMG-binding domain sidechain (A₁) is ##STR5## wherein R⁵ and R⁷ areindependently selected from hydrogen, lower alkyl, alkali metal ion andalkaline earth metal ion; and R⁶ is hydrogen or lower alkyl. SidechainA₁ is novel and forms an integral part of this invention.

A suitable dihydroxy acid binding domain sidechain (A₂) is ##STR6##wherein R⁶ is hydrogen or lower alkyl, R⁸ is hydrogen or lower alkyl infree acid form or in the form of a physiologically acceptable andhydrolyzable ester or δ lactone thereof (i.e., when A₂ is ##STR7## Inaddition, R⁸ can be alkali metal ion or alkaline earth metal ion.

A suitable linker (X) is --(CH₂)_(a) --, --CH═CH--, --C.tbd.C--, --CH₂O--, wherein O is linked to the phosphorous atom or the aromatic anchorwhen Am is A₁, and wherein O is linked to the aromatic anchor when Am isA₂, and wherein "a" is 1, 2, or 3.

Definitions of Terms

The terms "salt" and "salts" refer to basic salts formed with inorganicand organic bases. Such salts include ammonium salts; alkali metalsalts, such as lithium, sodium and potassium salts (which arepreferred); alkaline earth metal salts, such as calcium and magnesiumsalts; salts with organic bases, such as amine like salts (e.g.,dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, andhydrabamine salts); and salts with amino acids like arginine, lysine andthe like; and zwitterions, the so-called "inner salts". Nontoxic,pharmaceutically acceptable salts are preferred, although other saltsare also useful, e.g., in isolating or purifying the product.

The term "lower alkyl" or "alkyl" as employed herein alone or as part ofanother group includes both straight and branched chain hydrocarbons,containing 1 to 12 carbons in the normal chain or the various branchedisomers thereof, preferably 1 to 7 carbons, such as methyl, ethyl,propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl,heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl,undecyl, dodecyl, and the like, as well as such groups including one ormore substituents selected from halogen, (such as F, Br, Cl, and I),CF₃, aryl, cycloalkyl, alkoxy, hydroxy, alkylamino, alkanoylamino,carbonylamino, nitro, cyano, mercapto, and alkylthio.

The terms "cycloalkyl" and "cycloalkenyl" as employed herein alone or aspart of another group includes cyclic hydrocarbon groups containing 3 to12 carbons, preferably 3 to 8 carbons, which include cyclopropyl,cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, andcyclohexenyl, as well as groups substituted with 1 or 2 halogens, 1 or 2lower alkyl groups, 1 or 2 lower alkoxy groups, 1 or 2 hydroxy groups, 1or 2 alkylamino groups, 1 or 2 alkanoylamino groups, 1 or 2arylcarbonylamino groups, 1 or 2 amino groups, 1 or 2 nitro groups, 1 or2 cyano groups, 1 or 2 mercapto groups, and/or 1 or 2 alkylthio groups.

The terms "aryl" or "ar" as employed herein refer to monocyclic orbicyclic aromatic groups containing 6 to 10 carbons in the ring portion,such as phenyl, naphthyl, substituted phenyl or substituted naphthyl,wherein the substituents on either the phenyl or naphthyl may be alkyl,halogen (Cl, Br or F), CF₃, 1, 2 or 3 lower alkoxy groups, 1, 2 or 3aralkyl groups, 1, 2 or 3 hydroxy groups, 1, 2 or 3 phenyl groups, 1, 2or 3 alkanoyloxy groups, 1, 2 or 3 benzoyloxy groups, 1, 2 or 3halophenyl groups, 1, 2 or 3 alkyl groups, 1, 2 or 3 alkylamino groups,1, 2 or 3 alkanoylamino groups, 1, 2 or 3 arylcarbonylamino groups, 1, 2or 3 amino groups, 1, 2 or 3 nitro groups, 1, 2 or 3 cyano groups, and1, 2 or 3 thiol groups, with the aryl group preferably containing 3substituents.

The terms "aralkyl", "aryl-alkyl" or "aryl-lower alkyl" as used hereinalone or as part of another group refer to groups having at least onealkyl and at least one aryl group as defined above, such as benzyl, aswell as such groups having one or more substituents selected fromcycloalkyl, alkylcycloalkyl, amino, oxy, alkoxy, and adamantyl.

The term "alkenyl" by itself or as part of another groups refers to bothstraight and branched chain groups. Those groups having 2 to 10 carbonatoms are preferred. The term "alkenyl" further includes groups havingone or two halo substituents, an alkoxy substituent, an arylsubstituent, an alkyl-aryl substituent, a haloaryl substituent, acycloalkyl substituent, or an alkylcycloalkyl substituent.

The term "alkanoyl" as used herein as part of another group refers tolower alkyl linked to a carbonyl group.

The terms "halogen" or "halo" as used herein refer to chlorine, bromine,fluorine, and iodine, with chlorine and fluorine being preferred.

The term "halo substituted alkyl" refers to alkyl groups in which one ormore hydrogens have been replaced by chloro, bromo, or fluoro groups.

The term "heterocyclo" refers to fully saturated or unsaturated,monocyclic or bicyclic, aromatic or nonaromatic hydrocarbon groupshaving 5 or 6 atoms in each ring and at least one heteroatom. Theheterocyclo group has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, or 1 to4 nitrogen atoms in the ring. The bicyclic heterocyclo group maycomprise a benzene ring, provided that the bicyclic group is attached byway of an available carbon atom in the benzene ring. The heterocyclogroup may be substituted with halogen (Cl, Br or F), CF₃, 1, 2 or 3lower alkoxy groups, 1, 2, or 3 aralkyl groups, 1, 2 or 3 hydroxygroups, 1, 2 or 3 phenyl groups, 1, 2 or 3 alkanoyloxy groups, 1, 2 or 3benzoyloxy groups, 1, 2 or 3 halophenyl groups, 1, 2 or 3 alkyl groups,1, 2 or 3 alkylamino groups, 1, 2 or 3 alkanoylamino groups, 1, 2 or 3arylcarbonylamino groups, 1, 2 or 3 amino groups, 1, 2 or 3 nitrogroups, 1, 2 or 3 cyano groups, and 1, 2 or 3 thiol groups, with thearyl group preferably containing 3 groups, preferably having 3substituents. Exemplary heterocyclo groups are 2- and 3-thienyl, 2- and3-furyl, 2- and 3-pyrrolyl, 2-, 3- and 4-pyridyl, 2-, 4- and5-imidazolyl, 2- and 3-pyrrolidinyl, 2-, 3- and 4-piperidinyl, 2-, 3-and 4-azepinyl, 4, 5, 6 or 7-indolyl, 4, 5, 6 or 7-isoindolyl, 5, 6, 7or 8-quinolinyl, 5, 6, 7 or 8-isoquinolinyl, 4, 5, 6 or7-benzothiazolyl, 4, 5, 6 or 7-benzoxazolyl, 4, 5, 6 or7-benzimidazolyl, 4, 5, 6 or 7-benzoxadiazolyl, and 4, 5, 6 or7-benzofurazanyl.

Processes of Preparation

The compounds of the present invention are made generally in thefollowing manner.

The syntheses of aldehyde 5, which is the starting material forcompounds of the invention when R³ and R⁴ taken together can be(CH═CH)₂, are shown in Scheme 1. Reaction of anthranilonitrile 1 with anexcess of Grignard reagent (R¹ MgBr) in an aprotic solvent, such asether (Et₂ O) or tetrahydrofuran (THF), followed by acidic and basicwork-up affords keto-aniline 2. Friedlander condensation of 2 with anappropriately substituted β-keto-ester under acidic conditions (i.e. H₂SO₄ /HOAc/Δ, H₂ SO₄ /ethanol (EtOH)/Δ) provides quinoline 3. Reductionof the ester group in 3 with reducing agents such as LiAlH₄ or DIBAL-Hin inert solvents such as THF, Et₂ O, or toluene gives alcohol 4.Oxidants such as Dess-Martin periodinane or oxalylchloride/dimethylsulfoxide (DMSO)/triethylamine convert compound 4 toaldehyde 5. ##STR8##

The syntheses of aldehyde 10, which is the starting material forcompounds of the invention I wherein R₃ and R₄ are not (CH═CH)₂, areshown in Scheme 2. Condensation of ketone R³ COCH₂ R⁴ with aldehyde R¹CHO under either acidic or basic conditions (i.e. H₂ SO₄ /EtOH orEtONa/EtOH) provides α,β-unsaturated ketone 6. Michael addition of aβ-keto-ester to compound 6 under basic conditions (i.e. EtONa/EtOH,KOBut/EtOH, NaH/THF) gives 1,5-diketone 7.

Alternatively, compound 7 may be prepared by an additional route.Knoevenagel condensation of an appropriately substituted β-keto-esterwith aldehyde R¹ CHO (piperidine/HOAc/benzene/heat) provides compound11. Addition of a ketone enolate, generated by treatment of R³ COCH₂ R⁴with bases such as LDA, LiTMP, or LiN(TMS)₂ in an aprotic solvent suchas THF, to compound 11 gives 1,5-diketone 7.

Compound 8 is formed by treatment of compound 7 with NH₂ OH.HCl or NH₄OAc/Cu(OAc)₂ in hot HOAc. Reduction of the ester group in 8 with areducing agent such as LiAlH₄ or DIBAL-H in inert solvents such as THF,Et₂ O, or toluene gives alcohol 9. Oxidants such as Dess-Martinperiodinane or oxalyl chloride/DMSO/triethylamine convert compound 9 toaldehyde 10. ##STR9##

The synthesis of compounds I wherein Am is A₂ and X is CH═CH and CH₂ CH₂(Compounds 16 and 18) is described in Scheme 3. Reaction of aldehyde 12with cis-1-ethoxy-2-lithioethylene at low temperatures (-78° C.) in anappropriate solvent such as THF, followed by acidic work-up providesenal 13. Condensation of the dianion of methyl acetoacetate with enal 13in an aprotic solvent (THF, Et₂ O) affords compound 14. Compound 15 isobtained via stereoselective reduction of 14 with a trialkylborane and areducing agent such as NaBH₄ in a solvent such as THF containing MeOHand a small amount of catalyst such as O₂ or pivalic acid. Compound 15can be saponified to 16 using aqueous solutions of a metal hydroxide inan appropriate solvent (i.e. MeOH, dioxane). Additionally, 15 may behydrogenated to 17 in the presence of a suitable catayst (Pd, Pt, Ru)and solvent (MeOH, EtOAc, EtOH) and then saponified as described aboveto provide compound 18. ##STR10##

The synthesis of phosphinic acid derivatives I, wherein Am is A₁ and Xis C.tbd.C and CH₂ CH₂ (Compounds 24 and 26) is described in Scheme 4.Reaction of aldehyde 12 with carbon tetrabromide and triphenylphosphinein solvents such as CH₂ Cl₂ or CH₃ CN provides dibromide 19. Conversionof 19 to 20 is effected by treatment of 19 with alkyl lithium reagentssuch as n-BuLi at low temperature (-78° C.) in an aprotic solvent suchas THF. Conversely, 20 may be obtained directly from 12 utilizingdimethyl diazomethylphosphonate and KOBut in a solvent such as THF (-78°C. to room temperature). Metallation of 20 (RLi, THF, -78° C.) followedby treatment with the chiral phosphonochloridate 21 affords compound 22which can subsequently be desilylated (TBAF/HOAc) in an appropriatesolvent such as THF to provide 23. Compound 23 can be saponified to 24using aqueous solutions of a metal hydroxide in an appropriate solvent(i.e., MeOH, dioxane). Additionally, 23 may be hydrogenated to 25 in thepresence of a suitable catayst (Pd, Pt, Ru) and solvent (MeOH, EtOAc,EtOH) and then saponified as above to provide compound 26. ##STR11##

Scheme 5 describes the synthetic route to compounds I where Am is A₁ andX is CH═CH (e.g. compound 31. Treatment of acetylene 20 with neat Bu₃SnH in the presence of AIBN at an elevated temperature (i.e. 140° C.)affords trans- vinyl stannane 27. Compound 27 was converted to 28 byiodine treatment of 27 in an appropriate solvent such as Et₂ O or CHCl₃.Metallation of 28 (t-butylLi) at -78° C. in an aprotic solvent such asTHF gives the corresponding vinyl anion, which may be coupled withphosphonochloridate 21 at -100° C. to provide 29. Subsequently 29 may bedesilylated (TBAF/HOAc) in an appropriate solvent such as THF to provide30. Compound 30 can be saponified to 31 using aqueous solutions of ametal hydroxide in an appropriate solvent (e.g., MeOH, dioxane).##STR12##

The synthesis of compounds I wherein Am is A₂, X is CH═CH and n is 1(e.g., compound 35) is described in Scheme 6. Bis-silylation of compound15 with a bulky silylchloride (e.g., ClSi(t-butyl)Ph₂, ClSi(t-butyl)Me₂,ClSiPh₃) in the presence of a suitable base (e.g., TEA, imidazole,pyridine) and solvent (e.g., CH₂ Cl₂, THF) provides compound 32.Treatment of 32 with oxidants such as m-CPBA or CF₃ CO₃ H in anappropriate solvent such as CH₂ Cl₂ or HOAc affords N-oxide 33.Desilylation of 33 (TBAF/HOAc/THF or HF/CH₃ CN) gives 34, which may besaponified to 35 using aqueous solutions of a metal hydroxide in anappropriate solvent (e.g., MeOH, dioxane). ##STR13##

Additionally, compound 17 may be oxidized and saponified, as describedabove, to provide compounds I wherein Am is A₂, X is CH₂ CH₂ and n is 1(e.g., compound 37) as shown in Scheme 7. ##STR14##

Scheme 8 depicts the chemistry used to synthesize compounds I wherein Amis A₁ and n is 1 (e.g., compound 40). Treatment of 38 with oxidants suchas m-CPBA or CF₃ CO₃ H in an appropriate solvent such as CH₂ Cl₂ or HOAcaffords N-oxide 39. Compound 39 may be saponified to 40 using aqueoussolutions of a metal hydroxide in an appropriate solvent (i.e. MeOH,dioxane). ##STR15##

Reaction scheme 9 shows a preferred method for preparing the preferredquinolinealdehyde 5, which can be used as described in schemes 3 and 4to prepare a corresponding compound of formula I. Reagent 42 (wherein Mis lithium or magnesium halide) is reacted with anthranilonitrile 41 toform ketoaniline 43. Acylation of ketoaniline 43 with ethylmalonylchloride affords amide 44 ("Et" refers to ethyl). Ethanolic sodiumethoxide is used to cause Knoevenagel condensation of amide 44 to formquinoline ester 45. A reducing agent (e.g., lithium aluminum hydride)converts quinoline ester 45 to quinolinolmethanol 46. An oxidizing agent(e.g., manganese dioxide) converts compound 46 to aldehyde 47.Triflation of aldehyde 47 (e.g., with trifluoromethanesulfonicanhydride) affords aldehyde 48. Stannane 49 is prepared by reaction ofthe corresponding lithium or Grignard reagent with tri-n-alkyltinchloride in diethy ether at -78° C. Aldehyde 48 and stannane 49 undergopalladium-catalyzed coupling to form 2,4-substituted 3-quinolinealdehyde5. All reactions is scheme 9 take place under argon atmosphere.##STR16##

Scheme 10 describes the synthetic route to compounds I wherein Am is A₁and X is CH₂ O (e.g. compound 52). Reaction of alcohol 9 withphosphonochloridate 21 in a solvent such as pyridine affords phosphonate50. Compound 50 may be desilylated (HOAc/TBAF) in THF to give compound51. Saponification of 51 using aqueous solutions of a metal hydroxide inan organic solvent (e.g., MeOH, dioxane) provides compound 52. Furtherreaction conditions are described in Example 99. ##STR17##

Pharmaceutical Composition

A further aspect of the present invention is a pharmaceuticalcomposition consisting of at least one of the compounds of the presentinvention in association with a pharmaceutical vehicle or diluent. Thepharmaceutical composition can be formulated employing conventionalsolid or liquid vehicles of diluents and pharmaceutical additives of atype appropriate to the mode of desired administration. The compoundscan be administered by an oral route, for example, in the form oftablets, capsules, granules or powders, or they can be administered by aparenteral route in the form of injectable preparations, such dosageforms containing from 1 to 2000 mg of active compound per dosage, foruse in the treatment. The dose to be administered depends on the unitarydose, the symptoms, and the age and the body weight of the patient.

Use and Utility

The compounds of the present invention can be administered in a similarmanner as known compounds suggested for use in inhibiting cholesterolbiosynthesis, such as lovastatin, in mammalian species such as humans,dogs, cats and the like. Thus, the compounds of the invention may beadministered in an amount from about 4 to 2000 mg in a single dose or inthe form of individual doses from 1 to 4 times per day, preferably 4 to200 mg in divided dosages of 1 to 100 mg, suitably 0.5 to 50 mg 2 to 4times daily or in sustained release form.

Compounds containing dihydroxy acid HMG-CoA binding domain side chainsare prepared as racemic mixtures (3S*, 5R*) and may later be resolved toobtain the 3S, 5R isomer, which is preferred.

Phosphorus-containing HMG-CoA binding domain sidechains may be preparedas racemic mixtures and may later be resolved to obtain the S-isomer,which is preferred. However, these compounds may be prepared directly inthe form of their S-isomers as described herein and in the workingexamples set out hereinafter.

The compounds of the invention are inhibitors of3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and thus areuseful in inhibiting cholesterol biosynthesis as demonstrated by thefollowing tests.

1) Rat Hepatic HMG-CoA Reductase

Rat hepatic HMG-CoA reductase activity is measured using a modificationof the method described by Edwards (Edwards, P. A., et al., J. LipidRes. 20:40, 1979). Rat hepatic microsomes are used as a source ofenzyme, and the enzyme activity is determined by measuring theconversion of the ¹⁴ C-HMG-CoA substrate to ¹⁴ C-mevalonic acid.

a. Preparation of Microsomes

Livers are removed from 2-4 cholestyramine-fed, decapitated, SpragueDawley rats, and homogenized in phosphate buffer A (potassium phosphate,0.04M, pH 7.2; KCl, 0.05M; sucrose, 0.1M; EDTA, 0.03M; aprotinin, 500 KIunits/ml). The homogenate is spun at 16,000 × g for 15 minutes at 4° C.The supernatant is removed and recentrifuged under the same conditions asecond time. The second 16,000× g supernatant is spun at 100,000× g for70 minutes at 4° C. Pelleted microsomes are resuspended in a minimumvolume of buffer A (3-5 ml per liver), and homogenized in a glass/glasshomogenizer. Dithiothreitol is added (10 mM), and the preparation isaliquoted, quick frozen in acetone/dry ice, and stored at -80° C. Thespecific activity of the first microsomal preparation was 0.68 nmolemevalonic acid/mg protein/minute.

b. Enzyme Assay

The reductase is assayed in 0.25 ml which contains the followingcomponents at the indicated final concentrations:

    ______________________________________                                        0.04 M         Potassium phosphate, pH 7.0                                    0.05 M         KCl                                                            0.10 M         Sucrose                                                        0.03 M         EDTA                                                           0.01 m         Dithiothreitol                                                 3.5 mM         NaCl                                                           1%             Dimethylsulfoxide                                              50-200 μg   Microsomal protein                                             100 μM      .sup.14 C-[DL]HMG-CoA (0.05 μCi,                                           30-60 mCi/mmole)                                               2.7 mM         NADPH (nicotinamide adenine                                                   dinucleotide phosphate)                                        ______________________________________                                    

Reaction mixtures are incubated at 37° C. Under the conditionsdescribed, enzyme activity increases linearly up to 300 μg microsomalprotein per reaction mixture, and is linear with respect to incubationtime up to 30 minutes. The standard incubation time chosen for drugstudies is 20 minutes, which results in 12-15% conversion of HMG-CoAsubstrate to the mevalonic acid product. [DL-]HMG-CoA substrate is usedat 100 μM, twice the concentration needed to saturate the enzyme underthe conditions described. NADPH is used in excess at a level 2.7 timesthe concentration required to achieve maximum enzyme velocity.

Standardized assays for the evaluation of inhibitors are conductedaccording to the following procedure. Microsomal enzyme is incubated inthe presence of NADPH at 37° C. for 15 minutes. DMSO vehicle with orwithout test compound is added, and the mixture is further incubated for15 minutes at 37° C. The enzyme assay is initiated by adding ¹⁴C-HMG-CoA substrate. After 20 minutes of incubation at 37° C., thereaction is stopped by the addition of 25 μl of 33% KOH. ³ H-mevalonicacid (0.05 μCi) is added, and the reaction mixture is allowed to standat room temperature for 30 minutes. Fifty μl of 5N HCl is added tolactonize the mevalonic acid. Bromophenol blue is added as a pHindicator to monitor an adequate drop in pH. Lactonization is allowed toproceed for 30 minutes at room temperature. Reaction mixtures arecentrifuged for 15 minutes at 2800 rpm. The supernatants are layeredonto 2 grams AG 1-X 8 anion exchange resin (Biorad, formate form) pouredin 0.7 cm (id) glass columns, and eluted with 2.0 ml H₂ O. The first 0.5ml is discarded, and the next 1.5 ml is collected and counted for bothtritium and carbon 14 in 10.0 ml Opti-fluor scintillation fluid. Resultsare calculated as nmoles mevalonic acid produced per 20 minutes, and arecorrected to 100% recovery of tritium. Drug effects are expressed as I₅₀values (concentration of drug producing 50% inhibition of enzymeactivity) derived from composite dose response data with the 95%confidence interval indicated.

Conversion of drugs in lactone form to their sodium salts isaccomplished by solubilizing the lactone in DMSO, adding a 10-fold molarexcess of NaOH, and allowing the mixture to stand at room temperaturefor 15 minutes. The mixture is then partially neutralized (pH 7.5-8.0)using 1N HCl, and diluted into the enzyme reaction mixture.

2) Cholesterol Synthesis in Freshly Isolated Rat Hepatocytes

Compounds which demonstrate activity as inhibitors of HMG-CoA reductaseare evaluated for their ability to inhibit ¹⁴ C-acetate incorporationinto cholesterol in freshly isolated rat hepatocyte suspensions usingmethods originally described by Capuzzi et al., (Capuzzi, D. M. andMargolis, S., Lipids, 6:602, 1971).

a. Isolation of Rat Hepatocytes

Sprague Dawley rats (180-220 grams) are anesthetized with Nembutal (50mg/kg). The abdomen is opened and the first branch of the portal vein istied closed. Heparin (100-200 units) is injected directly into theabdominal vena cava. A single closing suture is placed on the distalsection of the portal vein, and the portal vein is canulated between thesuture and the first branching vein. The liver is perfused at a rate of20 ml/minute with prewarmed (37° C.), oxygenated buffer A (HBSS withoutcalcium or magnesium containing 0.5 mM EDTA) after severing the venacava to allow drainage of the effluent. The liver is additionallyperfused with 200 ml of prewarmed buffer B (HBSS containing 0.05%bacterial collagenase). Following perfusion with buffer B, the liver isexcised and decapsulated in 60 ml Waymouth's medium allowing free cellsto disperse into the medium. Hepatocytes are isolated by low speedcentrifugation for 3 minutes at 50× g at room temperature. Pelletedhepatocytes are washed once in Waymouth's medium, counted and assayedfor viability by trypan blue exclusion. These hepatocyte enriched cellsuspensions routinely show 70-90% viability.

b. ¹⁴ C-Acetate Incorporation into Cholesterol

Hepatocytes are resuspended at 5×10⁶ cells per 2.0 ml in incubationmedium (IM) [0.02M Tris-HCl (ph 7.4), 0.1M KCl, 3.3 mM sodium citrate,6.7 mM nicotinamide, 0.23 mM NADP, 1.7 mM glucose-6-phosphate].

Test compounds are routinely dissolved in DMSO or DMSO:H₂ O (1:3) andadded to the IM. Final DMSO concentration in the IM is ≦1.0%, and has nosignificant effect on cholesterol synthesis.

Incubation is initiated by adding ¹⁴ C-acetate (58 mCi/mmol, 2 μci/ml),and placing the cell suspensions (2.0 ml) in 35 mm tissue culturedishes, at 37° C. for 2.0 hours. Following incubation, cell suspensionsare transferred to glass centrifuge tubes and spun at 50× g for 3minutes at room temperature. Cell pellets are resuspended and lysed in1.0 ml H₂ O, and placed in an ice bath.

Lipids are extracted essentially as described by Bligh, E. G. and W. J.Dyer, Can. J. Biochem. and Physiol., 37:911, 1959. The lower organicphase is removed and dried under a stream of nitrogen, and the residueresuspended in (100 μl) chloroform:methanol (2:1). The total sample isspotted on silica gel (LK6D) thin-layer plates and developed inhexane:ethyl ether:acetic acid (75:25:1). Plates are scanned and countedusing a BioScan automated scanning system. Radiolabel in the cholesterolpeak (RF 0.28) is determined and expressed at total counts per peak andas a percent of the label in the total lipid extract. Cholesterol peaksin control cultures routinely contain 800-1000 cpm, and are 9-20% of thelabel present in the total lipid extract; results compatable withCapuzzi, et al., indicating 9% of extracted label in cholesterol.

Drug effects (% inhibition of cholesterol synthesis) are determined bycomparing % of label in cholesterol for control and drug treatedcultures. Dose response curves are constructed from composite data fromtwo or more studies, and results are expressed as I₁₀ values with a 95%confidence interval.

3) Cholesterol Synthesis in Human Skin Fibroblasts

Compound selectivity favoring greater inhibitory activity in hepatictissue would be an attribute for a cholesterol synthesis inhibitor.Therefore, in addition to evaluating cholesterol synthesis inhibitors inhepatocytes, these compounds are also tested for their activity asinhibitors of cholesterol synthesis in cultured fibroblasts.

a. Human Skin Fibroblast Cultures

Human skin fibroblasts (passage 7-27) are grown in Eagles' minimalessential medium (EM) containing 10% fetal calf serum. For eachexperiment, stock cultures are trypsinized to disperse the cellmonolayer, counted, and plated in 35 mm tissue culture wells (5×10⁵cells/2.0 ml). Cultures are incubated for 18 hours at 37° C. in 5% CO₂/95% humidified room air. Cholesterol biosynthetic enzymes are inducedby removing the serum containing medium, washing the cell monolayers,and adding 1.0 ml of EM containing 1.0% fatty acid free bovine serumalbumin, and incubating the cultures an additional 24 hours.

b. ¹⁴ C-Acetate Incorporation into Cholesterol

Induced fibroblast cultures are washed with EMEM₁₀₀ (Earle's minimalessential medium). Test compounds are dissolved in DMSO or DMSO:EM (1:3)(final DMSO concentration in cell cultures ≦1.0%), added to thecultures, and the cultures preincubated for 30 minutes at 37° C. in 5%CO₂ /95% humidified room air. Following preincubation with drugs, [1-¹⁴C]Na acetate (2.0 μCi/ml, 58 mCi/mmole) is added, and the culturesreincubated for 4 hours. After incubation, the culture medium isremoved, and the cell monolayer (200 μg cell protein per culture) isscraped into 1.0 ml of H₂ O. Lipids in the lysed cell suspension areextracted into chloroform:methanol as described for hepatocytesuspensions. The organic phase is dried under nitrogen, and the residueresuspended in chloroform:methanol (2:1) (100 μl), and the total samplespotted on silica gel (LK6D) thin-layer plates, and analyzed asdescribed for hepatocytes.

Inhibition of cholesterol synthesis is determined by comparing thepercentage of label in the cholesterol peak from control anddrug-treated cultures. Results are expressed as I₅₀ values, and arederived from composite dose response curves from two or moreexperiments. A 95% confidence interval for the I₅₀ value is alsocalculated from the composite dose response curves.

The following working Examples represent preferred embodiments of thepresent invention. Unless otherwise indicated, all temperatures areexpressed in degrees Centigrade.

Example 1 (3R*, 5S*,6E)-7-[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, monolithium salt

A. (E)-3-(4-fluorophenyl)-1-phenyl-2-propen-1-one

A mixture of acetophenone (7.02 gm, 58.4 mmol), p-fluorobenzaldehyde(7.24 gm, 58.4 mmol) and concentrated H₂ SO₄ (10 ml) in glacial HOAc(116 ml) was stirred at room temperature for 2 days. The solution waspoured into H₂ O (250 ml) and neutralized with 10% NaOH (200 ml). Theaqueous layer was extracted once with Et₂ O and the Et₂ O layer waswashed successively with H₂ O, saturated NaHCO₃ (2×) and brine, thendried (MgSO₄). Filtration and removal of the solvent afforded a yellowsolid which was recrystallized from hot hexane to give(E)-3-(4-fluorophenyl)-1-phenyl-2-propen-1-one (7.94 gm, 60%) as lightyellow needles.

m.p. 86°-88° C. TLC: R_(f) 0.36 (20% EtOAc in hexane)

B. β-(4-fluorophenyl)-α-(2-methyl-1-oxopropyl)-δ-oxobenzenepentanoicacid, ethyl ester

To a mixture of (E)-3-(4-fluorophenyl)-1-phenyl-2-propen-1-one (4.59 gm,20.3 mmol) and ethyl isobutyrylacetate (3.86 gm, 24.4 mmol) in absoluteEtOH (100 ml) was added a solution of EtONa in EtOH. The EtONa solutionwas prepared by dissolving Na metal (50 mg, 2.2 mmol) in EtOH (10 ml).After stirring at room temperature for 3 hours, additional ethylisobutyrylacetate (1.0 gm, 6.3 mmol) was added. Stirring continued foran additional 2 hours. The mixture was poured into a separatory funnelcontaining Et₂ O and saturated NH₄ Cl. The phases were shaken andseparated. The aqueous layer was extracted once with EtOAc and thecombined organic layers were washed with brine and dried (Na₂ SO₄).Filtration and removal of the solvent gave a solid/liquid mixture.Crystallization of the residue from hot hexane/EtOAc gaveβ-(4-fluorophenyl)-α-(2-methyl-1-oxopropyl)-δ-oxobenzenepentanoic acid,ethyl ester (5.91 gm, ˜95% one diastereomer) as colorless needles. Themother liquor was stripped and recrystallized from hot hexane to affordadditional product, giving a total of 7.21 gm (92%)β-(4-fluorophenyl)-α-(2-methyl-1-oxopropyl)-δ-oxobenzenepentanoic acid,ethyl ester as a 7:3:1 mixture of diastereomers.

m.p. (1st crop) 119.2°-120.8° C. TLC: R_(f) 0.22 and 0.18 (20% EtOAc inhexane)

C. 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxylicacid, ethyl ester

A mixture ofβ-(4-fluorophenyl)-α-(2-methyl-1-oxopropyl)-δ-oxobenzenepentanoic acid,ethyl ester (7.92 gm, 20.6 mmol) and hydroxylamine hydrochloride (4.32gm, 62.2 mmol) in glacial HOAc (100 ml) was refluxed for 2.5 hours. Thereaction was cooled to room temperature and poured into an ice coldsolution of concentrated NH₄ OH (140 ml) in H₂ O (400 ml). The resultingmixture was extracted twice with Et₂ O and the combined ethereal layerswere washed with brine, dried (Na₂ SO₄), filtered and stripped to yielda gummy orange-red oil. Flash chromatography of the oil (Merck SiO₂, 7%EtOAc in hexane) gave4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxylic acid,ethyl ester (4.88 gm, 65%) as a near colorless gum.

TLC: R_(f) 0.47 (20% EtOAc in hexane)

D. 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinemethanol

A slurry of LiAlH₄ (775 mg, 20.4 mmol) in dry Et₂ O (70 ml) at 0° C. wastreated with a solution of4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxylic acid,ethyl ester (4.80 gm, 13.2 mmol) in Et₂ O (5 ml). After 2.5 hours, thereaction was quenched and diluted with H₂ O and the aqueous layer wasextracted twice with Et₂ O and once with EtOAc. The combined organiclayers were washed with H₂ O and brine, then dried (Na₂ SO₄), filteredand stripped. The resulting solid was dissolved in hot EtOAc anddirectly chromatographed (flash, Merck SiO₂, 20% EtOAc in hexane) togive crude4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinemethanol.Recrystallization from hot hexane/EtOAc gave4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinemethanol (3.30gm) as a white solid. The mother liquor was stripped and recrystallizedagain to give an additional 230 mg of product (total 3.53 gm, 84%).

m.p. 167.2°-167.8° C. TLC: R_(f) 0.26 (20% EtOAc in hexane)

E.4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde

A solution of Dess-Martin periodinane (1.54 gm, 3.63 mmol) in dry CH₂Cl₂ (17 ml) was treated with t-butanol (267 mg, 3.60 mmol) and stirredfor 15 minutes at room temperature. A solution of4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinemethanol (895mg, 2.78 mmol) in CH₂ Cl₂ (12 ml) was then added and stirring wascontinued 30 minutes, after which time the mixture was quenched by theaddition of Et₂ O (70 ml) and 1N NaOH (35 ml). The biphasic mixture wasstirred for 10 minutes and the layers were separated. The organic layerwas washed with 1N NaOH, H₂ O and brine, then dried (Na₂ SO₄), filteredand stripped. The solid residue was chromatographed (Flash, Merck SiO₂,10% EtOAc in hexane) to afford pure4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde(782 mg, 88%) as a white solid. Analytically pure material was obtainedby recrystallization of the solid from a minimum amount of hot hexane.

m.p. 105°-107° C. TLC: R_(f) 0.50 (20% EtOAc in hexane)

F.(E)-3-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-2-propenal

n-BuLi (1.6M in hexanes, 1.52 ml, 2.43 mmol) was added to a solution ofcis-1-ethoxy-2-(tri-n-butylstannyl)ethylene (961 mg, 2.66 mmol) in dryTHF (7.5 ml) at -78° C. The mixture was stirred for 1 hour, then treatedwith a solution of4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde(708 mg, 2.22 mmol) in THF (3.5 ml). One hour after the addition, thereaction was immersed in an ice bath, stirred for 5 minutes, then themixture was quenched with H₂ O (8 ml) and 10% HCl (8 ml). The solutionwas stirred at room temperature for 2 hours, then basicified with 10%NaOH (10 ml) and extracted twice with Et₂ O. The combined Et₂ O layerswere washed with H₂ O and brine, dried (Na₂ SO₄), then filtered andstripped to give a yellow oil. Chromatographic purification of the oil(Flash, Merck SiO₂, 10% EtOAc in hexane) gave(E)-3-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-2-propenal(665 mg, 87%) as a white solid. Recrystallization from hot hexane gaveanalytically pure material (580 mg).

m.p. 113.8°-114.4° C. TLC: R_(f) 0.35 (20% EtOAc in hexane)

G.(E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-5-hydroxy-3-oxo-6-heptenoicacid, methyl ester

Methyl acetoacetate (272 mg, 2.34 mmol) was added dropwise to a slurryof NaH (60% in mineral oil, 93.7 mg, 23.4 mmol) in dry THF (5.5 ml) at0° C. After 15 minutes, the solution was treated with n-BuLi (1.6M inhexanes, 1.11 ml, 1.78 mmol) and stirred an additional 15 minutes.(E)-3-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-2-propenal(560 mg, 1.62 mmol) in THF (3.0 ml) was added, resulting in an orangesolution. After 25 minutes, the solution was poured into a biphasicmixture Et₂ O (30 ml), 1N HCl (4.5 ml) and H₂ O (16 ml). The aqueousphase was neutralized with saturated NaHCO₃ and the layers wereseparated. The aqueous layer was extracted again with Et₂ O and thecombined Et₂ O layers were washed with brine and dried (Na₂ SO₄).Filtration and solvent removal afforded an oil which was chromatographed(Flash, Merck SiO₂, 30% EtOAc in hexane) to give(E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-5-hydroxy-3-oxo-6-heptenoicacid, methyl ester (387 mg, 52%) as a light yellow oil.

TLC: R_(f) 0.31 (40% EtOAc in hexane)

H. (3R, 5S,6E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, methyl ester

A solution of(E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-5-hydroxy-3-oxo-6-heptenoicacid, methyl ester (357 mg, 0.77 mmol) in THF (12 ml) was treated withtriethylborane (1.0M in THF, 1.62 ml, 1.62 mmol). Twenty fivemilliliters of air was bubbled through the solution and the mixture wasstirred at room temperature for 30 minutes. The solution was cooled to-78° C. and treated with NaBH₄ (29.4 mg, 0.78 mmol) followed by dropwiseaddition of dry methanol (1.90 ml). After stirring at -78° C. for 1.5hours, the mixture was quenched with 30% H₂ O₂ (3.5 ml) in H₂ O (11 ml).The mixture was kept at -78° C. for 15 minutes, then warmed to roomtemperature and stirred for 30 minutes. The solution was poured into 50%saturated NaHCO₃ and extracted with Et₂ O (3×). The Et₂ O extracts werecombined, washed with H₂ O, saturated NaHCO₃ and brine, then dried (Na₂SO₄). Filtration and removal of the solvent gave a yellow oil which waschromatographed (Flash, Merck SiO₂, 40% EtOAc in hexane) to afford (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, methyl ester (320 mg, 89%) as a colorless oily foam.

TLC: R_(f) 0.17 (40% EtOAc in hexane)

I. (3R*, 5S*,6E)-7-[4-Fluorophenyl)-2-(1-methyl-ethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, monolithium salt

A solution of (3R, 5S,6E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, methyl ester (290 mg, 0.625 mmol) in dioxane (4.0 ml) and H₂ O(4.0 ml) was treated with 1N LiOH (0.75 ml) at room temperature. After20 minutes, the solvent was evaporated and the residue waschromatographed on HP-20 (25 mm×90 mm column) eluting in succession withH₂ O (150 ml), 25% CH₃ CN in H₂ O (100 ml) and 50% CH₃ CN in H₂ O (200ml). The desired fractions were pooled and evaporated and the residuewas taken up in H₂ O and lyophilized to give (3R*, 5S*,6E)-7-[4-Fluorophenyl)-2-(1-methyl-ethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoic acid, monolithium salt(265 mg, 91%) as a white solid.

TLC: R_(f) 0.50 (8:1:1, CH₂ Cl₂ :HOAc:MeOH)

Example 2 (3R*, 5S*,6E)-7-[4-(4-Fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, monolithium salt

A. α-acetyl-β-(4-fluorophenyl)-δ-oxobenzenepentanoic acid, ethyl ester

To a mixture of (E)-3-(4-fluorophenyl)-1-phenyl-2-propen-1-one (4.62 gm,20.4 mmol) (the preparation of which is described in Example 1 and ethylacetoacetate (5.32 gm, 40.9 mmol) in absolute EtOH (100 ml) was added asolution of EtONa in EtOH. The EtONa solution was prepared by dissolvingNa metal (65 mg, 2.8 mmol) in EtOH (10 ml). A precipitate formed after 4hours of stirring. After 6 hours, the reaction was diluted with asolution of HOAc (170 mg) in H₂ O (100 ml), stirred for 5 minutes, thenfiltered. The solid was washed with H₂ O and dried overnight in vacuo toafford α-acetyl-β-(4-fluorophenyl)-δ-oxobenzenepentanoic acid, ethylester (6.12 gm) in ˜60-65% purity. This material was used directly inthe next reaction.

TLC: R_(f) 0.15 (20% EtOAc in hexane)

B. 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinecarboxylic acid, ethylester

A mixture of α-acetyl-β-(4-fluorophenyl)-δ-oxobenzenepentanoic acid,ethyl ester (6.12 gm) and hydroxylamine hydrochloride (3.61 gm, 52 mmol)in glacial HOAc (83 ml) was refluxed for 1 hour. The reaction was cooledto room temperature and poured into an ice cold solution of concentratedNH₄ OH (115 ml) in H₂ O (300 ml). The resulting mixture was extractedtwice with Et₂ O and the combined Et₂ O layers were washed with brine,dried (Na₂ SO₄), filtered and stripped to yield a dark gummy residue.The residue was chromatographed (Flash, Merck SiO₂, 8% EtOAc in hexane)to give 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinecarboxylic acid,ethyl ester which was rechromatographed (8% EtOAc in hexane) to affordpyridine 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinecarboxylic acid,ethyl ester (1.652 gm, 24% from(E)-3-(4-fluorophenyl)-1-phenyl-2-propen-1-one) in >90% purity.

TLC: R_(f) 0.35 (20% EtOAc in hexane)

C. 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinemethanol

A slurry of LiAlH₄ (305 mg, 8.04 mmol) in dry Et₂ O (30 ml) at 0° C.treated with a solution of4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinecarboxylic acid, ethylester (1.587 gm, 4.73 mmol) in Et₂ O (4 ml). After 50 minutes, thereaction was quenched and diluted with H₂ O and the solution wasadjusted to neutral pH with 10% HCl. EtOAc was added to dissolvesuspended product into the Et₂ O layer and the mixture was subsequentlyextracted three times with EtOAc. The combined organic layers werewashed with H₂ O and brine, then dried (Na₂ SO₄), filtered and strippedto give a yellow solid. Recrystallization of the solid from hothexane/acetone afforded4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinemethanol (916 mg) as awhite solid. An additional 283 mg of4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinemethanol was obtained byevaporation of the mother liquor followed by recrystallization of theresidue from hot hexane/EtOAc, giving a total of 1.199 gm (86%) product.

m.p. 181°-183° C. TLC: R_(f) 0.29 (40% EtOAc in hexane)

D. 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinecarboxaldehyde

A solution of Dess-Martin periodinane (1.04 gm, 2.45 mmol) in dry CH₂Cl₂ (12 ml) was treated with t-butanol (182 mg, 2.46 mmol) and stirredat room temperature for 15 minutes. A slurry of4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinemethanol (555 mg, 1.89mmol) in CH₂ Cl₂ (10 ml) and CH₃ CN (2 ml) was then added and stirringwas continued for 25 minutes. The mixture was diluted with Et₂ O (50 ml)and poured into 1N NaOH (25 ml) and stirred for 5 minutes. The phaseswere separated and the organic layer was washed successfully with 1NNaOH, H₂ O, and brine, then dried (Na₂ SO₄). Filtration and removal ofthe solvent afforded a solid. The solid was dissolved in hothexane/EtOAc and the resulting solution was cooled to 0° C., filteredand stripped to give a residue which was chromatographed (Flash, MerckSiO₂, 20% EtOAc in hexane).4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinecarboxaldehyde wasobtained as a white solid (458 mg, 83%). Analytically pure material wasobtained by recrystallization from hot hexane.

m.p. 119.5°-120.5° C. TLC: R_(f) 0.37 (20% EtOAc in hexane)

E. (E)-3-[4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-2-Propenal

n-BuLi (1.6M in hexanes, 1.52 ml, 2.43 mmol) was added to a solution ofcis-1-ethoxy-2-(tri-n-butylstannyl) ethylene (1.06 gm, 2.94 mmol) in dryTHF (7.5 ml) at -78° C. The mixture was stirred for 11/4 hours, thencooled to -100° C. (liquid N₂ /methanol) and treated with a solution of4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinecarboxaldehyde (707 mg,2.43 mmol) in THF (3.0 ml). Forty-five minutes after the addition, thetemperature was raised to -78° C. and the mixture was stirred for anadditional 50 minutes. The solution was then stirred in an ice bath for5 minutes and subsequently quenched with H₂ O (8 ml) and 10% HCl (8 ml).After stirring at room temperature for 1.5 hours, the mixture was madebasic with 10% NaOH (10 ml) and extracted twice with Et₂ O. The combinedEt₂ O layers were washed with H₂ O and brine, dried (Na₂ SO₄), filteredand stripped to yield a solid. The solid was washed with cold Et₂ O. TheEt₂ O washings were stripped and triturated with cold hexane to giveadditional solid, which was pooled with the above solid to give 586 mg(76%)(E)-3-[4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-2-propenal.Analytically pure material was obtained by recrystallization from hothexane/EtOAc.

m.p. 160.5°-163° C. TLC: R_(f) 0.17 (20% EtOAc in hexane)

F.(E)-7-[4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-5-hydroxy-3-oxo-6-heptenoicacid, methyl ester

Methyl acetoacetate (324 mg, 2.79 mmol) was added dropwise to a slurryof NaH (60% in mineral oil, 111.7 mg, 2.79 mmol) in dry THF (7 ml) at 0°C. After 15 minutes, n-BuLi (1.5M in hexanes, 1.46 ml, 2.19 mmol) wasadded and the mixture was stirred an additional 15 minutes. Addition ofa solution of(E)-3-[4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-2-propenal (633mg, 1.99 mmol) in THF (7 ml) to the reaction mixture resulted in theformation of a bright red solution. Twenty minutes after the addition,the solution was poured into a biphasic mixture of Et₂ O (40 ml) and 1NHCl (5.5 ml) in H₂ O (20 ml). The aqueous layer was made basic withsaturated NaHCO₃ and the phases were separated. The aqueous layer wasextracted again with Et₂ O, neutralized with 1N HCl and extracted oncemore. The combined Et₂ O layers were washed with brine, dried (Na₂ SO₄),filtered and stripped to yield an oil. Flash chromatography (Merck SiO₂,1:1 EtOAc:hexane) afforded(E)-7-[4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-5-hydroxy-3-oxo-6-heptenoicacid, methyl ester (251 mg, 29%) as a yellow oil

TLC: R_(f) 0.16 (40% EtOAc in hexane)

G. (3R*, 5S*,6E)-7-[4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, methyl ester

A solution of(E)-7-[4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-5-hydroxy-3-oxo-6-heptenoicacid, methyl ester (235 mg, 0.54 mmol) in THF (8 ml) was treated withtriethylborane (1.0M in THF, 1.13 ml, 1.13 mmol). Twenty milliliters ofair was bubbled through the solution and the mixture was stirred at roomtemperature for 25 minutes. The solution was cooled to -78° C. andtreated with NaBH₄ (20.7 mg, 0.55 mmol) followed by dropwise addition ofdry methanol (1.25 ml). After stirring at -78° C. for 1.5 hours, themixture was quenched with 30% H₂ O₂ (3.5 ml) in H₂ O (8 ml). The mixturewas kept at -78° C. for 15 minutes, then warmed to room temperature andstirred for 30 minutes. The solution was poured into 50% saturatedNaHCO₃ and extracted with Et.sub. 2 O (3×). The combined Et₂ O extractswere washed with H₂ O, saturated NaHCO₃ and brine, then dried (Na₂ SO₄),filtered and stripped. Purification of the resulting oil (Flash, MerckSiO₂, 70% EtOAc/30% hexane) gave (3R*, 5S*,6E)-7-[4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, methyl ester (188 mg, 80%) as a colorless oily foam.

TLC: R_(f) 0.17 (60% EtOAc/40% hexane)

H. (3R*, 5S*,6E)-7-[4-(4-Fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, monolithium salt

A solution of (3R*, 5S*,6E)-7-[4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, methyl ester (186 mg, 0.47 mmol) in dioxane (3.0 ml) and H₂ O (3.0ml) was treated with 1N LiOH (0.51 ml) at room temperature. After 25minutes, the solvent was evaporated and the residue was chromatographedon HP-20 (25 mm×90 mm column) eluting in succession with H₂ O (150 ml),25% CH₃ CN in H₂ O (100 ml), and 50% CH₃ CN in H₂ O (200 ml). Thedesired fractions were pooled and evaporated and the residue was takenup in H₂ O and lyophilized to give (3R*, 5S*,6E)-7-[4-(4-Fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, monolithium salt (174 mg, 93%) as a white solid.

TLC: R_(f) 0.29 (8:1:1, CH₂ Cl₂ :HOAc:MeOH)

Example 3 (3R*, 5S*,6E)-7-[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, monolithium salt

A. 3-hydroxy-4-methyl-1-phenyl-1-pentanone

Acetophenone (11.433 gm, 95 mmol) was added dropwise over a five minuteperiod to a solution of lithium bis(trimethylsilyl)amide (1.0M in THF,100 ml, 100 mmol) in THF (50 ml) kept at -78° C. After 30 minutes,isobutyraldehyde (6.87 gm, 95 mmol) was added dropwise and stirring wascontinued for an additional hour. The mixture was quenched withsaturated NH₄ Cl (100 ml), warmed to room temperature, diluted with H₂ Oand extracted 2× with Et₂ O. The combined Et₂ O extracts were washedwith brine, dried (Na₂ SO₄), filtered and stripped to yield an oil. Theoil was distilled (P=1.5 mm) and the fraction boiling between 120°-124°C. was chromatographed (flash, Merck SiO₂, 15% EtOAc in hexane) to givethe desired 3-hydroxy-4-methyl-1-phenyl-1-pentanone as a colorlessliquid (9.13 gm, 50%)

TLC: R_(f) 0.20 (20% EtOAc in hexane)

B. (E)-4-methyl-1-phenyl-2-penten-1-one

A mixture of 3-hydroxy-4-methyl-1-phenyl-1-pentanone (8.400 gm, 43.7mmol) and p-toluenesulfonic acid (820 mg, 4.3 mmol) in benzene (210 ml)was refluxed in a Dean-Stark apparatus for 10 minutes. The solution wascooled, diluted with Et₂ O, and washed with saturated NaHCO₃ and brine.Filtration and removal of the solvent afforded a yellow oil which wassubsequently distilled (P=2.0 mm, 97°-100° C.) to give the(E)-4-methyl-1-phenyl-2-penten-1-one (6.94 gm) as a colorless liquid. ¹H-NMR analysis showed the distillate to be 78% the desired product and22% the β, δ-unsaturated isomer. The material was used directly for thenext reaction.

TLC: R_(f) 0.35 (10% EtOAc in hexane)

C. α-(4-fluorobenzoyl)-β-(1-methylethyl)-δ-oxobenzenepentanoic, ethylester

A mixture of (E)-4-methyl-1-phenyl-2-penten-1-one (6.32 gm crude, 4.93gm pure, 28.3 mmol) and ethyl 4-fluorobenzoyl acetate (5.95 gm, 28.3mmol) in EtOH (120 ml) was treated with a solution of EtONa (3.3 mmol)in EtOH (10 ml) at room temperature. After stirring 3.5 hours, thesolution was treated with 73 mg of MeONa. Stirring was continued for anadditional 3 hours. The solution was quenched with saturated NH₄ Cl (80ml), diluted with H₂ O, and extracted 3× with Et₂ O. The combined Et₂ Oextracts were washed with brine and subsequently dried (Na₂ SO₄),filtered and stripped to give a yellow residue. The residue was purifiedby flash chromatography (Merck SiO₂, 50×260 mm column, 3% acetone inhexane) to give a diastereomeric mixture of theα-(4-fluorobenzoyl)-β-(1-methylethyl)-δ-oxobenzene-pentanoic, ethylester as a viscous oil (6.99 gm, 64%).

TLC: R_(f) 0.04 (5% acetone in hexane)

D. 2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinecarboxylicacid, ethyl ester

A mixture ofα-(4-fluorobenzoyl)-β-(1-methylethyl)-δ-oxobenzenepentanoic, ethyl ester(6.967 gm, 18.12 mmol) and hydroxylamine hydrochloride (3.778 gm, 54.4mmol) in glacial HOAc (82 ml) was refluxed under argon for 2 hours. Thecooled solution was added to an ice cold mixture of concentrated NH₄ OH(120 ml) in H₂ O (200 ml). The resulting mixture was extracted twicewith Et₂ O and the combined Et₂ O extracts were washed with brine, dried(Na₂ SO₄), filtered and stripped to yield a orange-red oil.Chromatographic purification of the oil (flash, Merck SiO₂, 3% EtOAc inhexane) gave2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinecarboxylic acid,ethyl ester as a colorless viscous oil (3.482 gm, 53%)

TLC: R_(f) 0.39 (10% EtOAc in hexane)

E. 2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinemethanol

To a slurry of LiAlH₄ (1.457 gm, 38.4 mmol) in dry THF at 0° C. wasadded a solution of2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinecarboxylic acid,ethyl ester (3.37 gm, 9.27 mmol) in THF (7 ml). After 4.5 hours, theflask was charged with an additional 0.88 gm LiAlH₄ and stirring wascontinued for 2 more hours. The mixture was quenched with H₂ O anddiluted with H₂ O and EtOAc. The phases were shaken and separated, andthe aqueous layer was extracted again with EtOAc and Et₂ O. The pooledorganic layers were washed with H₂ O and brine, then dried (Na₂ SO₄),filtered and stripped to give a white solid. The solid wasrecrystallized from hot EtOAc/hexane to afford2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinemethanol aswhite crystals. The mother liquor was stripped and recrystallized againfrom hot EtOAc/hexane to give a total of 2.684 gm (90%) desired product.

m.p. 172.5°-173.5° C. TLC: R_(f) 0.17 (20% EtOAc in hexane)

F.2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde

t-Butanol (175 mg, 2.35 mmol) was added to a stirring solution ofDess-Martin periodinane (1.005 gm, 2.37 mmol) in dry CH₃ CN (15 ml).After 15 minutes, a solution of2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinemethanol (582mg, 1.81 mmol) in CH₃ CN (9 ml) and CH₂ Cl₂ (3 ml) was added to themixture and stirring was continued for 40 minutes. The mixture wasdiluted with Et₂ O and quenched with 1N NaOH (25 ml). After 25 minutesof rapid mixing, the biphasic mixture was separated and the aqueouslayer was extracted with Et₂ O. The combined organic layers were washedin succession with 1N NaOH, H₂ O, and brine, then dried (Na₂ SO₄),filtered and stripped to yield a solid residue. The residue waschromatographed (Merck SiO₂, 30% hexane in CH₂ Cl₂) to give2-(4-fluorophenyl)-4-(1-methylethyl)- 6-phenyl-3-pyridinecarboxaldehydeas a white solid (532 mg, 92%). An analytical sample was obtained byrecrystallization from a minimum amount of hot hexane.

m.p. 115.5°-117.0° C. TLC: R_(f) 0.43 (20% EtOAc in hexane)

G.(E)-3-[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]-2-propenal

n-BuLi (1.6M in hexane, 554 ul, 0.83 mmol) was added to a solution ofcis-1-ethoxy-2-(tri-n-butylstannyl)ethylene (333 mg, 0.92 mmol) in dryTHF (4 ml) at -78° C. The mixture was stirred at -78° C. for one hour,then cooled to -100° C. (liquid N₂ /MeOH) and treated with a solution of2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde(221 mg, 0.69 mmol) in THF (2 ml). One hour after the addition, thetemperature was raised to -78° C. and the solution was stirred for anadditional one hour. TLC analysis indicated that the reaction wasincomplete so an additional amount of the vinyl anion reagent (generatedfrom 317 mg vinyl tin reagent, 370 ul of 1.6M n-BuLi and 4 ml THF) wasadded via canula at -78° C. the resulting solution stirred an additional45 minutes. The mixture was warmed to 0° C., stirred for 15 minutes,then quenched with H₂ O (6 ml) and 10% HCl (6 ml). After one hour ofvigorous mixing, the solution was made basic with 10% NaOH (12 ml) andextracted twice with Et₂ O. The combined Et₂ O layers were washed withH₂ O and brine, dried (Na₂ SO₄), filtered and stripped to yield a yellowoil. Chromatographic purification (flash, Merck SiO₂, 40% hexane in CH₂Cl₂ followed by straight CH₂ Cl₂ afforded(E)-3-[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]-2-propenal(141 mg, 59%) as a light yellow foam.

TLC: R_(f) 0.24 (20% EtOAc in hexane)

H.(E)-7-[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]-5-hydroxy-3-oxo-6-heptenoicacid, methyl ester

Methyl acetoacetate (160 mg, 1.38 mmol) was dropwise to a slurry of NaH(60% in mineral oil, 55.1 mg, 1.38 mmol) in dry THF (3.5 ml) at 0° C.After 15 minutes, n-BuLi (1.5M in hexane, 830 ul, 1.25 mmol) was addedand the mixture was stirred an additional 15 minutes. The bright yellowsolution was cooled to -78° C. and treated with a solution of(E)-3-[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]-2-propenal(317 mg, 0.92 mmol) in THF (2 ml). Stirring continued for 20 minutes,after which time the reaction was warmed to 0° C. and stirred for anadditional 20 minutes. The yellow-orange solution was then added to abiphasic mixture of 1N HCl (3 ml), H₂ O (15 ml), and Et₂ O (30 ml). Theaqueous layer was made slightly basic with saturated NaHCO₃ and thephases were separated. The aqueous layer was diluted with saturated NH₄Cl and was extracted with Et₂ O once again. The combined organic layerswere washed with brine and dried (Na₂ SO₄). Filtration and removal ofthe solvent afforded an oil which was chromatographed (flash, MerckSiO₂, 35% EtOAc in hexane) to give(E)-7-[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]-5-hydroxy-3-oxo-6-heptenoicacid, methyl ester as an oily solid (187 mg, 44%).

TLC: R_(f) 0.21 (40% EtOAc in hexane)

I. (3R*, 5S*,6E)-7-[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, methyl ester

A solution of(E)-7-[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]-5-hydroxy-3-oxo-6-heptenoicacid, methyl ester (182 mg, 0.39 mmol) in THF (5.5 ml) was treated withtriethylborane (1.0N in THF, 830 ul, 0.83 mmol). Twenty milliliters ofair was bubbled through the solution and the mixture was stirred at roomtemperature for 30 minutes. The solution was cooled to -78° C. andtreated with NaBH₄ (15.0 mg, 0.40 mmol) followed by dropwise addition ofdry methanol (0.9 ml). After stirring at -78° C. for 1.75 hours, themixture was quenched with 30% H₂ O₂ (2.8 ml) in H₂ O (6 ml). The mixturewas kept at -78° C. for 15 minutes, then warmed to room temperature andstirred for 45 minutes. The solution was poured into 50% saturatedNaHCO₃ and extracted with Et₂ O (2×). The combined Et₂ O extracts werewashed with saturated NaHCO₃, H₂ O, and brine, then dried (Na₂ SO₄),filtered and stripped. Purification of the resulting oil (flash, MerckSiO₂, 50% EtOAc in hexane) gave (3R*, 5S*,6E)-7-[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, methyl ester (157 mg, 86%) as a colorless oily foam.

TLC: R_(f) 0.27 (60% EtOAc/40% hexane)

J. (3R*, 5S*,6E)-7-[2-(4-Fluorophenyl)-4-(1-methyl-ethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, monolithium salt

A solution of (3R*, 5S*,6E)-7-[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, methyl ester (152 mg, 0.33 mmol) in dioxane (3 ml) and H₂ O (3 ml)was treated with 1N LiOH (360 ul) at room temperature. After 30 minutes,the solvent was evaporated and the residue was chromatographed on HP-20eluting in succession with H₂ O (150 ml), 25% CH₃ CN in H₂ O (100 ml),and 50% CH₃ CN in H₂ O (200 ml). The desired fractions were pooled andevaporated and the residue was taken up in H₂ O and lyophilized to give(3R*, 5S*,6E)-7-[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, monolithium salt (147 mg, 94%) as a white solid.

TLC: R_(f) 0.22 (20:1:1, CH₂ Cl₂ :HOAc:MeOH)

Example 4(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A.3-(2,2-dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridine

A solution of carbon tetrabromide (2.204 gm, 6.65 mmol) in CH₂ Cl₂ (8ml) was added over a 12 minute period to a cold (-12° C.) solution of4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde(1.415 gm, 4.43 mmol) (the preparation of which is described inExample 1) and triphenylphosphine (3.488 gm, 13.3 mmol) in CH₂ Cl₂ (25ml). After the addition was complete, the cooling bath was removed andthe mixture was stirred for 20 minutes. The solution was quenched withsaturated NaHCO₃ and extracted 3× with CH₂ Cl₂. The combined organiclayers were washed with saturated NaHCO₃, dried (Na₂ SO₄), filtered andstripped to give a yellow oil. The oil was chromatographed (flash, MerckSiO₂, 40% CH₂ Cl₂ in hexane) to give3-(2,2-dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridineas a colorless foam (2.152 gm, 100%).

TLC: R_(f) 0.53 (20% EtOAc in hexane)

B. 3-ethynyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridine

A solution of3-(2,2-dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridine(2.105 gm, 4.43 mmol) in dry THF (23 ml) was cooled to -78° C. andtreated with n-BuLi (1.5M in hexane, 5.95 ml, 8.93 mmol) over a 4 minuteperiod. After stirring at -78° C. for 1.25 hours, the deep purplesolution was quenched with saturated NH₄ Cl, warmed to room temperature,diluted with H₂ O, and extracted 2× with Et₂ O. The combined Et₂ Oextracts were washed with brine, dried (Na₂ SO₄), filtered and strippedto give a yellow solid. The solid was recrystallized from a minimumamount of hot hexane to afford analytically3-ethynyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridine as whiteneedles. The mother liquor was stripped and recrystallized again fromhot hexane to give additional product (total yield 1.199 gm, 86%)

TLC: R_(f) 0.31 (20% CH₂ Cl₂ in hexane)

C.(S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-[[[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]butanoicacid, methyl ester

(S)-4-(Hydroxymethoxyphosphinyl)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester, dicyclohexylamine (1:1) salt (4.501 gm, 7.123 mmol)was partitioned between EtOAc and 5% KHSO₄. The EtOAc layer was washed3× with 5% KHSO₄, then with brine, then dried (Na₂ SO₄), filtered andstripped to give a colorless oil (phosphinic acid monomethyl ester). Theoil was dissolved in dry CH₂ Cl₂ (15 ml) and treated withN,N-diethyltrimethylsilylamine (2.70 ml, 2.07 gm, 14.25 mmol). Afterstirring at room temperature for one hour, the solvent was removed invacuo and the residue was azeotroped with dry benzene (20 ml). Theresidue was re-dissolved in dry CH₂ Cl₂ (15 ml), cooled to -12° C. andtreated with 2 drops DMF and oxalyl chloride (700 ul, 1.018 gm, 8.02mmol). After 15 minutes, the solution was warmed to room temperature andstirred for an additional 45 minutes. The solvent was stripped and theyellow residue (phosphinylchloridate) was azeotroped with benzene (20ml) and dried in vacuo (oil pump) for 30 minutes.

Meanwhile, a solution of acetylene 3 (1.321 gm, 4.19 mmol) in THF (10ml) at -78° C. was treated with n-BuLi (1.5M in hexane, 2.8 ml, 4.2mmol) and the resulting deep green mixture was stirred for 30 minutes.The acetylenic anion solution was added dropwise via canula over a 20minute period to a -78° C. solution of the phosphinylchloridate in THF(9 ml). The resulting yellow-brown mixture was stirred at -78° C. for 40minutes, then quenched with 50% saturated NH₄ Cl. The solution waswarmed to room temperature, diluted with H₂ O, and poured into saturatedNaHCO₃. The aqueous phase was extracted 3× with Et₂ O. The combined Et₂O layers were washed with brine, dried (Na₂ SO₄), filtered and stripped.The residue was chromatographed (flash, Merck SiO₂, 30% EtOAc in hexane)to afford(S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-[[[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]butanoicacid, methyl ester as a colorless foam (2.316 gm, 74%).

TLC: R_(f) 0.30 (40% EtOAc in hexane)

D.(S)-4-[[[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-ethynyl]methoxy-phosphinyl]-3-hydroxybutanoicacid, methyl ester

A mixture of(S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-[[[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]butanoicacid, methyl ester (800 mg, 1.07 mmol), tetra-n-butylammonium fluoride(1.0M in THF, 3.21 ml, 3.21 mmol), and HOAc (325 mg, 5.41 mmol) in THF(12 ml) was stirred at room temperature for 17 hours. The solution wascooled to 0° C., diluted with H₂ O, and extracted twice with EtOAc. Thepooled EtOAc layers were washed with saturated NaHCO₃ and brine. Theorganic layer was then washed twice 5% KHSO₄, then with H₂ O and brine.Drying (Na₂ SO₄), followed by filtration and removal of the solventafforded a yellow oil. The oil was dissolved in Et₂ O (10 ml) andtreated with excess diazomethane for 20 minutes. The excess diazomethanewas destroyed by the addition of HOAc and the solvent was removed invacuo. The residue was chromatographed (flash, Merck SiO₂, 50×70 mmcolumn 35% acetone in hexane (650 ml) followed by 1:1 acetone:hexane) toafford(S)-4-[[[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester (463 mg, 85%) as a colorless foam.

TLC: R_(f) 0.38 (1:1 acetone:hexane)

E.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A solution of(S)-4-[[[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester (446 mg, 0.875 mmol) in dioxane (7 ml) was treatedwith 1N LiOH (2.63 ml, 2.63 mmol) at room temperature and the mixturewas subsequently heated at 55° C. under argon for one hour. The solventwas evaporated and the residue was chromatographed on HP-20 eluting insuccession with H₂ O (200 ml), 25% MeOH in H₂ O (100 ml), 50% MeOH in H₂O (200 ml), and 50% CH₃ CN in H₂ O (100 ml). The desired fractions werepooled and evaporated and the residue was taken up in H₂ O andlyophilized to give(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt (416 mg, 94%) as a white solid.

TLC: R_(f) 0.46 (7:2:1,i-PrOH,NH₄ OH,H₂ O)

Example 5(S)-4-[[[2-(4-Fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A. 1-(2-aminophenyl)-2-methyl-1-propanone

A solution of anthranilonitrile (8.507 gm, 72 mmol) in dry Et₂ O (20 ml)was added to i-propylmagnesium chloride (2.0M in Et₂ O, 100 ml, 200mmol) in dry Et₂ O (30 ml) at 0° C. over a 15 minute period. After theaddition was complete, the mixture was warmed to room temperature andstirred for 4.5 hours. The solution was cooled to 0° C., quenched with10% HCl (150 ml), then stirred for 25 minutes. The aqueous layer wasmade basic with solid NaOH (25 gm) and then extracted with Et₂ O (3×).The combined Et₂ O extracts were washed with brine, then dried (Na₂SO₄), filtered and stripped to give a yellow oil. Flash Chromatographyof the oil (Merck SiO₂, 15% EtOAc in hexane) afforded1-(2-aminophenyl)-2-methyl-1-propanone (10.916 gm, 93%) as a goldenyellow oil.

TLC: R_(f) 0.32 (20% EtOAc in hexane)

B. 2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinoline-carboxylic acid,ethyl ester

A mixture of 1-(2-aminophenyl)-2-methyl-1-propanone (5.526 gm, 33.9mmol), ethyl p-fluorobenzoylacetate (7.12 gm, 33.9 mmol) andconcentrated H₂ SO₄ (0.34 ml) in glacial HOAc (34 ml) was refluxed for22 hours. The reaction mixture was cooled to room temperature and pouredinto an ice-cold solution of concentrated NH₄ OH (48 ml) in H₂ O (120ml). The resulting mixture was extracted twice with Et₂ O and thecombined Et₂ O layers were washed with H₂ O and brine, then dried (Na₂SO₄), filtered and stripped to yield a cloudy brown oil. Flashchromatography (Merck SiO₂, 10% EtOAc in hexane) afforded impure2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinoline-carboxylic acid, ethylester as an oil. Most of the volatile impurities were distilled offunder an oil pump vacuum (bath temp. 85° C.), leaving a yellow oil(5.096 gm) which was 77% by weight2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinecarboxylic acid, ethylester (34% effective yield).

TLC: R_(f) 0.36 (20% EtOAc in hexane)

C. 2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinoline-methanol

A solution of ester2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinoline-carboxylic acid, ethylester (5.00 gm crude, 3.85 gm pure, 114 mmol) in dry Et₂ O (5 ml) wasadded to a slurry of LiAlH₄ (1.41 gm, 37.1 mmol) in Et₂ O (70 ml) at 0°C. After 6.5 hours, the solution was quenched and diluted with H₂ O andthe aqueous layer was extracted with Et₂ O (3×). The combined Et₂ Oextracts were washed with brine, then dried (Na₂ SO₄), filtered andstripped to yield a semi-solid yellow residue. The residue wascrystallized from hot hexane/EtOAc to give2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinemethanol as whiteneedles. The mother liquor was stripped, dissolved in CH₂ Cl₂ (50 ml)and treated with N-chlorosuccinamide (700 mg). After 15 minutes, thesolution was concentrated, diluted with Et₂ O and washed first withsaturated NaHCO₃, then with a solution of Na₂ SO₃ in saturated NaHCO₃.The solvent was removed and the residue was chromatographed (flash,Merck SiO₂, 30% EtOAc in hexane) to give additional2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinoline-methanol as an impureorange semi-solid. Recrystallization from hot hexane/EtOAc gave thedesired product as white needles. The pooled solids were recrystallizedonce again to give analytically pure2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinemethanol (1.17 gm, 35%).

m.p. 208°-210° C. TLC: R_(f) 0.42 (40% EtOAc in hexane)

D. 2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinecarboxaldehyde

Dess-Martin periodinane (1.002 gm, 2.36 mmol) was dissolved in dry CH₂Cl₂ (11 ml), treated with t-butanol (175 mg, 2.36 mmol) and theresulting mixture was stirred at room temperature for 15 minutes. Aslurry of 2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinemethanol (505mg, 1.71 mmol) in CH₂ Cl₂ (8 ml) was then added. After 1.5 hours, thesolution was diluted with Et₂ O and 1N NaOH (25 ml), then stirred anadditional 10 minutes. The aqueous layer was separated and extractedonce with Et₂ O. The combined Et₂ O layers were washed with saturatedNaHCO₃ and brine, then dried (Na₂ SO₄), filtered and stripped to give anoil. Chromatographic purification (Flash, Merck SiO₂, 20% EtOAc inhexane) afforded aldehyde2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinecarboxaldehyde (430 mg,86%) as a colorless oil which solidified in the freezer.

TLC: R_(f) 0.40 (20% EtOAc in hexane)

E. 3-(2,2-dibromoethenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)quinoline

A solution of carbon tetrabromide (2.958 gm, 8.92 mmol) in CH₂ Cl₂ (10ml) was added over a 15 minute period to a cold (-10° C.) solution of2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinecarboxaldehyde (1.744gm, 5.95 mmol) (the preparation of which is described in Example 2) andtriphenylphosphine (4.680 gm, 17.84 mmol) in CH₂ Cl₂ (34 ml). After theaddition was complete, the mixture was stirred for 20 minutes thenquenched with saturated NaHCO₃ and extracted 3× with CH₂ Cl₂. Thecombined organic layers were washed with brine, dried (Na₂ SO₄),filtered and stripped to give a yellow-orange oil. The oil waschromatographed (flash, Merck SiO₂, 30% CH₂ Cl₂ in hexane followed by1:1 CH₂ Cl₂ in hexane followed by straight CH₂ Cl₂) to give3-(2,2-dibromoethenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)quinoline asa colorless foam (2.572 gm, 96%)

TLC: R_(f) 0.37 (20% EtOAc in hexane)

F. 3-ethynyl-2-(4-fluorophenyl)-4-(1-methylethyl)quinoline

A solution of3-(2,2-dibromoethenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)quinoline(2.563 gm, 5.71 mmol) in dry THF (30 ml) was cooled to -78° C. andtreated with n-BuLi (1.5M in hexane, 8.0 ml, 12 mmol) over a 5 minuteperiod. After stirring at -78° C. for 1.25 hours, the brown solution wasquenched with saturated NH₄ Cl, warmed to room temperature, diluted withH₂ O, and extracted 2× with Et₂ O. The combined Et₂ O extracts werewashed with brine, dried (Na₂ SO₄), filtered and stripped to give ayellow solid. The solid was recrystallized from hot hexane to affordanalytically pure3-ethynyl-2-(4-fluorophenyl)-4-(1-methylethyl)quinoline as off-whitecrystals (1.205 gm, 73%).

TLC: R_(f) 0.44 (20% CH₂ Cl₂ in hexane)

G.(S)-3-[[(1,1-dimethylethyl)diphenylsilyl]-oxy]-4-[[[2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethynyl]methoxyphosphinyl]butanoicacid, methyl ester

(S)-4-(Hydroxymethoxyphosphinyl)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester, dicyclohexylamine (1:1) salt (4.501 gm, 7.123 mmol)(4.390 gm, 6.95 mmol) was partitioned between EtOAc and 5% KHSO₄. TheEtOAc layer was washed 3× with 5% KHSO₄, then with brine, then dried(Na₂ SO₄), filtered and stripped to give a colorless oil (phosphinicacid monomethyl ester). The oil was dissolved in dry CH₂ Cl₂ (12 ml) andtreated with N,N-diethyltrimethylsilylamine (2.70 ml, 2.07 gm, 14.25mmol). After stirring at room temperature for 1.75 hours, the solventwas removed in vacuo and the residue was azeotroped with dry benzene (20ml). The residue was dissolved in dry CH₂ Cl₂ (12 ml), cooled to -10° C.and treated with 2 drops DMF and oxalyl chloride (670 ul). After 15minutes, the solution was warmed to room temperature and stirred for anadditional 50 minutes. The solvent was then stripped and the yellowresidue (phosphinylchloridate) was azeotroped with benzene (20 ml) anddried in vacuo (oil pump) for 30 minutes.

Meanwhile, a solution of3-ethynyl-2-(4-fluorophenyl)-4-(1-methylethyl)quinoline (1.180 gm, 4.08mmol) in THF (10 ml) at -78° C. was treated with n-BuLi (1.5M in hexane,2.75 ml, 4.13 mmol) and the resulting brown mixture was stirred for 30minutes. The acetylenic anion solution was added dropwise via canulaover a 15 minute period to a -78° C. solution of thephosphinylchloridate in THF (9 ml). The resulting yellow-brown mixturewas stirred at -78° C. for 45 minutes, then quenched with 50% saturatedNH₄ Cl. The solution was warmed to room temperature, diluted with H₂ O,and poured into saturated NaHCO₃. The aqueous phase was extracted 2×with Et₂ O. The combined Et₂ O layers were washed with brine, dried (Na₂SO₄), filtered and stripped. The cloudy brown residue waschromatographed (flash, Merck SiO₂, 40% EtOAc in hexane followed by 1:1EtOAc:hexane) to afford(S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-[[[2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethynyl]methoxyphosphinyl]butanoicacid, methyl ester as a colorless foam (1.898 gm, 64%).

TLC: R_(f) 0.14 (40% EtOAc in hexane)

H.(S)-4-[[[2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

A mixture of(S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-[[[2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethynyl]methoxyphosphinyl]butanoicacid, methyl ester (729 mg, 0.997 mmol), tetra-n-butylammonium fluoride(1.0M in THF, 3.0 ml, 3.0 mmol), and HOAc (304 mg, 5.06 mmol) in THF (12ml) was stirred at room temperature for 20 hours. The solution wascooled to 0° C., quenched with 5% KHSO₄, and extracted twice with EtOAc.The pooled EtOAc layers were washed twice with 5% KHSO₄ and once withbrine. The combined aqueous layers were back-extracted 3× with EtOAc andpooled with the initial EtOAc extracts. Drying (Na₂ SO₄), followed byfiltration and removal of the solvent afforded a yellow oil. The oil wasdissolved in Et₂ O and EtOAc and treated with excess diazomethane for 30minutes. The excess diazomethane was destroyed by the addition of HOAcand solvent was removed in vacuo. The residue was chromatographed(flash, Merck SiO₂, 40% acetone in hexane) to afford(S)-4-[[[2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethynyl]-methoxyphosphinyl]-3-hydroxybutanoic acid, methylester (349 mg, 72%) as a white oily foam.

TLC: R_(f) 0.38 (1:1 acetone:hexane)

I.(S)-4-[[[2-(4-Fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A solution of(S)-4-[[[2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethynyl]-methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester (333 mg, 0.689 mmol) in dioxane (5.5 ml) was treatedwith 1N LiOH (2.08 ml, 2.08 mmol) at room temperature and the mixturewas subsequently heated at 55° C. under argon for one hour. The solventwas evaporated and the residue was chromatographed on HP-20 eluting insuccession with H₂ O (200 ml), 25% MeOH in H₂ O (100 ml), and 50% MeOHin H₂ O (250 ml). The desired fractions were pooled and evaporated andthe residue was taken up in H₂ O and lyophilized to give(S)-4-[[[2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt (314 mg, 92%) as a white solid.

TLC: R_(f) 0.46 (7:2:1, i-PrOH, NH₄ OH, H₂ O)

Example 6(S)-4-[[2-[4-[4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A.[3S,4(Z)]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl)-3-pyridinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester and(S)-3-[[1,1-dimethylethyl)diphenylsilyl]oxy]-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl)-3-pyrindinyl]ethyl]methoxyphosphinyl]butanoicacid, methyl ester

(S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-[[[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]butanoicacid, methyl ester (1.016 gm, 1.36 mmol) (the preparation of which isdescribed in Example 4) was dissolved in MeOH (20 ml) and the mixturewas purged with argon. Platinum on carbon (5% pt/C, 316 mg) was thenadded and the mixture was hydrogenated in a Parr apparatus at 40 psi for16 hours. The solution was filtered through Celite and the filtrate wasstripped and chromatographed (flash, Merck SiO₂, 20% acetone in hexane)to give the[3S,4(Z)]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl)-3-pyridinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester (795 mg, 78%) as a colorless foam. In addition, thedesired (S)-3-[[1,1-dimethylethyl)diphenylsilyl]oxy]-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl)-3-pyrindinyl]ethyl]methoxyphosphinyl]butanoic acid, methylester was also obtained (95 mg, 9%) as a colorless oil.

[3S,4(Z)]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl)-3-pyridinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester (781 mg, 1.04 mmol) was dissolved in MeOH, and thesolution was treated with 5% Pt/C (386 mg) and hydrogenated at 40 psi ina Parr apparatus for 4 days. Filtration and removal of the solventafforded a residue which was chromatographed (flash, Merck SiO₂, 20%acetone in hexane) to give the desired saturated(S)-3-[[1,1-dimethylethyl)diphenylsilyl]oxy]-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl)-3-pyrindinyl]ethyl]methoxyphosphinyl]butanoicacid, methyl ester (144 mg, 18%) along with unreacted[3S,4(Z)]-3-[[(1,1-dimethylethyl)diphenylsilyl]-oxy]-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl)-3-pyridinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester (546 mg). [3S,4(Z)]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl)-3-pyridinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester:

TLC: R_(f) 0.16 (20% acetone in hexane)

(S)-3-[[1,1-dimethylethyl)diphenylsilyl]oxy]-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl)-3-pyrindinyl]ethyl]methoxyphosphinyl]butanoicacid, methyl ester:

TLC: R_(f) 0.09 (20% acetone in hexane)

B.(S)-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

A mixture of(S)-3-[[1,1-dimethylethyl)diphenylsilyl]oxy]-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl)-3-pyrindinyl]ethyl]methoxyphosphinyl]butanoicacid, methyl ester (278 mg, 0.37 mmol), tetra-n-butylammonium fluoride(1.0M in THF, 1.1 ml, 1.1 mmol), and HOAc (111 mg, 1.85 mmol) in THF (4ml) was stirred at room temperature for 18 hours. The solution wasquenched with cold H₂ O and extracted twice with EtOAc. The pooled EtOAclayers were washed with saturated NaHCO₃ and brine. Drying (Na₂ SO₄),followed by filtration and removal of the solvent afforded an oil. Theoil was chromatographed (flash, Merck SiO₂, 50% acetone in hexanefollowed by 70% acetone in hexane) to afford(S)-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester (168 mg, 88%) as a colorless foam.

TLC: R_(f) 0.18 (1:1 acetone:hexane)

C.(S)-4-[[2-[4-[4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A solution of(S)-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-ethyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester (177 mg, 0.345 mmol) of dioxane (3.5 ml) was treatedwith 1N LiOH (1.05 ml, 1.05 mmol) at room temperature and the mixturewas subsequently heated at 57° C. under argon for 1.3 hours. The solventwas evaporated and the residue was chromatographed on HP-20 eluting insuccession with H₂ O (300 ml), 25% MeOH in H₂ O (100 ml), and 50% MeOHin H₂ O (250 ml). The desired fractions were pooled and evaporated andthe residue was taken up in H₂ O and lyophilized to give(S)-4-[[2-[4-[4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt (156 mg, 85%) as a white solid.

TLC: R_(f) 0.40 (7:2:1, i-PrOH, NH₄ OH, H₂ O)

Example 7(S,E)-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A.(E)-4-(4-Fluorophenyl)-3-(2-iodoethenyl)-2-(1-methylethyl)-6-phenylpyridin

A mixture of3-Ethynyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridine (1.500gm, 4.76 mmol) (The preparation of which is described in example 4) and14 mg of AIBN in tri-n-butylstannyl hydride (Bu₃ SnH) (1.90 ml) wasrapidly heated to 120° C. After 4 minutes of heating, the mixture wastreated with additional Bu₃ SnH (0.4 ml) and the temperature of thereaction was raised to 130° C. Approximately 14 mg of AIBN was added tothe reaction mixture 0.5, 1.5 and 2.5 hours after heating was initiated.After 4 hours, the mixture was cooled to room temperature, diluted withEt₂ O (40 ml) and treated with solid I₂ (1.92 gm, 7.56 mmol). The darkreaction mixture was stirred for 1.5 hours, then quenched with 10% Na₂SO₃ in saturated NaHCO₃. The layers were shaken and separated. Theethereal layer was washed with brine, dried (Na₂ SO₄), filtered andstripped to yield a yellow oil. Flash chromatography (Merck SiO₂, 1%EtOAc in hexane followed by 1.5% EtOAc in hexane afforded(E)-4-(4-Fluorophenyl)-3-(2-iodoethenyl)-2-(1-methylethyl)-6-phenylpyridineas a solid. Recrystallization of the solid from hot hexane gave 1.438 gm(E)-4-(4-Fluorophenyl)-3-(2-iodoethenyl)-2-(1-methylethyl)-6-phenylpyridine.An additional 0.19 gm of compound was obtained from the mother liquor togive a total of 1.628 gm (77%) product.

m.p. 111.0°-112.3° C. TLC: R_(f) 0.28 (2% EtOAC in hexane)

B.(S,E)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester

(S)-4-(Hydroxymethoxyphosphinyl)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester, dicyclohexylamine (1:1) salt (2.000 gm, 3.17 mmol),the preparation of which is described at the end of this example 7, waspartitioned between EtOAc and 5% KHSO₄. The EtOAc layer was washed 3×with 5% KHSO₄, then with brine, then dried (Na₂ SO₄), filtered andstripped to give a colorless oil (phosphinic acid monomethyl ester). Theoil was dissolved in dry CH₂ Cl₂ (7 ml) and treated withN,N-diethyltrimethylsilylamine (1.20 ml, 0.92 gm, 6.33 mmol). Afterstirring at room temperature for one hour, the solvent was removed invacuo and the residue was azeotroped with dry benzene (10 ml). Theresidue was dissolved in dry CH₂ Cl₂ (7 ml), cooled to 10° C. andtreated with 1 drop DMF and oxalyl chloride (320 ul). After 15 minutes,the solution was warmed to room temperature and stirred for anadditional 50 minutes. The solvent was then stripped and the yellowresidue (phosphinylchloridate) was azeotroped with benezene (20 ml) anddried in in vacuo (oil pump) for 30 minutes.

Meanwhile, a solution of(E)-4-(4-Fluorophenyl)-3-(2-iodoethenyl)-2-(1-methylethyl)-6-phenylpyridine(827 mg, 1.86 mmol) in THF (2 ml) was added over a 2 minute period to a-78° C. solution of t-butyllithium (1.7M in pentane, 2.20 ml 3.74 mmol)in THF (7 ml). The resulting deep red solution was stirred for 25minutes then cooled to -100° C. The vinyl anion solution was added overa 30 second period to a -100° C. solution of the phosphinylchloridate inTHF (9 ml). The resulting orange mixture was stirred at -100° C. for 5minutes and at -78° C. for 30 minutes, then quenched with 50% saturatedNH₄ Cl. The solution was warmed to room temperature, diluted with H₂ O,and poured into saturated NaHCO₃. The aqueous phase was extracted 2×with Et₂ O. The combined Et₂ O layers were washed with brine, dried (Na₂SO₄), filtered and stripped. The resulting yellow oil waschromatographed (flash, Merck SiO₂, 15% acetone in hexane followed by20% acetone in hexane) to afford(S,E)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester as an off-white foam (826 mg, 59%).

TLC: R_(f) 0.28 (20% acetone in hexane)

C.(S,E)-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

A solution of(S,E)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester (826 mg, 1.10 mmol) in THF (10 ml) was treated withHOAc (320 ul, 336 mg, 5.6 mmol) and tetra-n-butylammonium fluoride (1.0Min THF, 3.3 ml, 3.3 mmol). After stirring at room temperature for 22hours, the solution was poured into saturated NaHCO₃ and extracted withEtOAc. The EtOAc extract was washed with brine, dried (Na₂ SO₄),filtered, and stripped to give an oil which was subsequentlychromatographed (flash, Merck SiO₂, 30% acetone in hexane followed by50% acetone in hexane).(S,E)-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester (497 mg, 88%) was obtained as a white oily foam.

TLC: R_(f) 0.40 (1:1 acetone:hexane)

D.(S,E)-4-[[2-[4-(4-Fluorophenyl)-2-(1-methethyl)-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A solution of(S,E)-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester (474 mg, 0.93 mmol) in dioxane (5 ml) was treatedwith 1N LiOH (3.0 ml, 3.0 mmol) at room temperature and the mixture wassubsequently heated at 55° C. under argon for 1.5 hours. The solvent wasevaporated and the residue was chromatographed on HP-20 eluting insuccession with H₂ O (200 ml), 25% MeOH in H₂ O (100 ml), and 50% MeOHin H₂ O (200 ml). The desired fractions were pooled and evaporated andthe residue was taken up in H₂ O and lyophilized to give(S,E)-4-[[2-[4-(4-Fluorophenyl)-2-(1-methethyl)-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt (431 mg, 89%) as a white solid.

TLC: R_(f) 0.48 (7:2:1, i-PrOH, NH₄ OH, H₂ O)

(S)-4-(Hydroxymethoxyphosphinyl)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester, dicyclohexylamine (1:1) salt

(1) (S)-4-Bromo-3-hydroxybutanoic acid, methyl ester

(1)(a) [R-(R*,R*)]-2,3,4-trihydroxybutanoic acid, calcium salt, hydrate

Ref. Carbohydrate Research 72, pp. 301-304 (1979).

Calcium carbonate (50 g) was added to a solution of D-isoascorbic acid(44.0 g, 250 mmol) in H₂ O (625 ml), the suspension cooled to 0° C. (icebath) and treated portionwise with 30% H₂ O₂ (100 ml). The mixture wasstirred at 30°-40° C. (oil bath) for 30 minutes. Darco (10 g) was addedand the black suspension heated on a steam bath until evolution of O₂ceased. The suspension was filtered through Celite, evaporated in vacuo(bath temperature 40° C.). The residue was taken up in H₂ O (50 ml),warmed on a steam bath and CH₃ OH was added until the solution wasturbid. The gummy precipitated solid was collected by filtration and airdried to give 30.836 g (75.2%) of desired calcium salt as a powderywhite solid.

TLC: (7:2:1) iPrOH-NH₄ OH-H₂ O, Rf=0.19, PMA.

(1)(b) [S-(R*,S*)]-2,4-Dibromo-3-hydroxybutanoic acid, methyl ester

Ref. Bock, K. et al., Acta Scandinavica (B) 37, pp. 341-344 (1983).

Part (1)(a) calcium salt (30 g) was dissolved in 30-32% HBr in aceticacid (210 ml) and stirred at room temperature for 24 hours. Methanol(990 ml) was then added to the brown solution and it was stirredovernight. The mixture was evaporated to an orange oil, taken up in CH₃OH (75 ml), refluxed for 2.0 hours and evaporated. The residue waspartitioned between EtOAc (100 ml) and H₂ O, the organic phase washedwith H₂ O (2×) and brine then dried over anhydrous Na₂ SO₄ andevaporated to give 22.83 g (90.5%) of crude dibromide as a light orangeoil.

TLC: (1:1) EtOAc-Hex, Rf=0.69, UV & PMA.

(1)(c) (S)-4-Bromo-3-hydroxybutanoic acid, methyl ester

Ref. the same as for preparation of (1)(b).

An argon-purged solution of the dibromide (20.80 g, 75.4 mmol) andanhydrous NaOAc (21.0 g) in EtOAc (370 ml) and glacial HOAc (37 ml) wastreated with 1.30 g of 5% Pd/C and the black suspension stirred under H₂(1 atm) while monitoring H₂ uptake. After 2.0 hours H₂ uptake wascomplete, the mixture was filtered through Celite, the filtrate washedwith saturated NaHCO₃ and brine then dried over anhydrous MgSO₄ andevaporated to give crude dibromoester as a brown oil. The crude oil wascombined with another batch (starting from 36.77 g of the dibromide) andvacuum distilled to give 25.77 g (61.3%) of desired title bromoester asa clear oil with b.p.=79°-80° C. (1.0 mm Hg).

TLC: (1:1) EtOAc-Hex, Rf=0.44, PMA. Anal Calcd for C₅ H₉ O₃ Br: C,30.48; H, 4.60; Br, 40.56 Found: C, 29.76; H, 4.50; Br, 39.86

(2) (S)-4-Bromo-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoic acid,methyl ester

A solution of part (1)(c) bromohydrin (4.0 g, 20.4 mmol), imidazole(6.94 g, 5.0 eg.), and 4-dimethylamino pyridine (4-DMAP) (12 mg, 0.005eg.) in dry DMF (40 ml) was treated with t-butyldiphenylsilyl chloride(5.84 ml, 1.1 eg.) and the homogeneous mixture stirred overnight underargon at room temperature. The mixture was partitioned between 5% KHSO₄and EtOAc, the organic phase washed with H₂ O and brine, dried overanhydrous Na₂ SO₄ and evaporated to give 9.32 g (100%) of crude silylether as a clear, viscous oil.

TLC: (3:1) Hex-EtOAc, Rf silyl ether=0.75, U.V. and PMA.

(3) (S)-4-Iodo-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoic acid,methyl ester

A solution of the crude Part 2 bromide (9.32 g, 201 mole) in methylethyl ketone (60 ml, dried over 4 Å sieves) was treated with sodiumiodide (15.06 g, 100.5 mole, 5.0 eq.) and the yellow suspension refluxedfor 5.0 hours under argon. The mixture was cooled, diluted with EtOAc,filtered, the filtrate washed with dilute NaHSO₃ (until colorless) andbrine then dried over anhydrous Na₂ SO₄ and evaporated in vacuo to give10.17 g of a yellow oil. The crude oil was purified by flashchromatography on silica gel (600 g) eluting with (3:1) Hexane-CH₂ Cl₂.Product fractions were combined and evaporated to give 7.691 g (74.2%,overall yield for both steps) of desired title iodide as a clear,colorless, viscous oil.

TLC: (3:1) Hex-EtOAc, product. Rf=0.75, U.V. and PMA. (Note: productiodide co-spots with starting bromide).

(4)(S)-4-Diisopropyloxyphosphinyl)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-butanoicacid, methyl ester

The Part (3) iodide (45.1 mmol., 21.70 g) was stirred under high vacuumfor 30 minutes. Freshly distilled triisopropyl phosphite (0.451 mol.,93.92 g, 113.37 ml.) was added in one portion and the reaction mixturewas stirred under argon and heated in a 155° C. oil bath for 16.5 hours.The mixture was then cooled to room temperature. Excess triisopropylphosphite and volatile reaction products were removed by short pathdistillation (10 mm Hg) followed by Kugelrohr distillation (0.50 mm Hg,100° C., 8 hours). The product was further purified via flashchromatography (95 mm diam. column, 6"/Merck silica gel, 6/3/1Hexane/acetone/toluene eluent, 2"/min flow rate, 50 ml fractions) toafford 17.68 g (33.96 mmol, 75% yield) of the title isopropylphosphonateas a clear viscous oil.

TLC: Silica gel Rf=0.32 (6:3:1 Hexane/acetone toluene) ¹ HNMR: (270MH_(z), CDCl₃) δ 7.70-7.65 (m,4H) 7.45-7.35 (m,6H) 4.57-4.44 (m,3H) 3.59(s,3H) 2.94 and 2.88 (2xd, 1H J=3.7 Hz) 2.65 and 2.60 (2xd, 1H J=7.4 Hz)2.24-1.87 (Series of m, 2H) 1.19 and 1.12 (2xd, 12H J=6.3 Hz) 1.01 (s,9H)

(5)(S)-4-(Hydroxymethoxyphosphinyl)-3-[[(1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester, dicyclohexylamine (1:1) salt

The Part (4) isopropyl phosphonate (30.5 mmol, 10.66 g) was stirredunder argon, at room temperature, in 80 ml of dry CH₂ Cl₂. This solutionwas treated dropwise (5 min) with bis-trimethylsilyltrifluoroacetamide(BSTFA) (32.8 mmol, 8.44 g, 8.71 ml), followed by dropwise addition (10min) of trimethylsilylbromide (TMSBr) (51.3 mmol), 7.84 g, 6.75 ml).After stirring at room temperature for 20 hours, the reaction mixturewas quenched with 200 ml of 5% aqueous KHSO₄ and stirred vigorously for15 minutes. The aqueous layer was extracted 3 times with ethylacetate.The organic extracts were combined, washed once with brine, dried overNa₂ SO₄ and concentrated in vacuo. The residue was azeotroped 2 timeswith 50 ml of toluene. The precipitate which formed was suspended intoluene and filtered. The filtrate was concentrated and theazeotrope/filter process repeated. The resulting filtrate was evaporatedin vacuo and then pumped under high vacuum for 5 hours. The resultingviscous clear oil was stirred under argon, at room temperature, in 50 mlof dry pyridine. This solution was treated in one portion withdicyclohexylcarbodiimide (DCC) (22.6 mmol, 4.65 g), followed by additionof methanol (41.0 mmol, 1.31 g, 1.67 ml). After stirring at roomtemperature for 20 hours, the reaction mixture was filtered through aCelite pad in a sintered glass funnel. The Celite was washed with ethylacetate and the combined filtrates were evaporated in vacuo. The residuewas redissolved in ethyl acetate and washed 2 times with 5% aqueousKHSO₄ and once with brine. The organic extract was dried over Na₂ SO₄,filtered, the filtrate concentrated and azeotroped 2 times with toluene,suspended in toluene and filtered. The resulting filtrate was againconcentrated, azeotroped, filtered and the filtrate evaporated in vacuoand place under high vacuum for 6 hours to afford the phosphonatemonoester as a clear viscous oil (10.2 g, >100% yield). TLC: silica gelR_(f) =0.50 (7:2:1 nPrOH/NH₄ OH/H₂ O). The phosphonate monoester [1.21 gwas pumped under high vacuum for 4 hours, affording 1.16 g (2.57 mmol)]was dissolved in 10 ml of dry ethyl ether and treated dropwise withdicyclohexylamine (2.65 mmol, 0.481 g, 0.528 ml). The resultinghomogeneous solution sat at room temperature for 7 hours resulting insignificant crystal formation. The mixture was stored at -20° C. for 16hours and then warmed to room temperature and filtered. The crystalswere washed with cold, dry ethyl ether and then pumped under high vacuumover P₂ O₅ for 18 hours. The crystals were subsequently pumped underhigh vacuum at 45° C. for 4 hours, affording 1.25 g (1.98 mmol, 77%yield) of the title dicyclohexylamine salt as a white powdery solid,m.p. 155°-156° C.

TLC: Silica gel R_(f) =0.57 (20% MeOH/CH₂ Cl₂) ¹ H NMR: (270 MH₂, CDCl₃)7.71-7.65 (m, 4H) 7.40-7.32 (m, 6H) 4.02 (m, 1H) 3.52 (s, 3H) 3.28 and3.22 (m, 1H) 3.11 (d, 3H J=11 Hz) 2.77-2.64 (m, 2H) 2.62-2.56 (m, 1H)1.92-1.08 (Series of m, 22H) 1.00 (S, 9H) Mass Spec: (FAB) 632 (M&H)⁺IR: (KBr) 3466-3457 (broad) 3046, 3016, 2997, 2937, 2858, 2836, 2798,2721, 2704, 2633, 2533, 2447, 1736, 1449, 1435, 1426, 1379, 1243, 1231,1191, 1107, 1074, 1061, 1051, 820 CM-1 Anal Calcd for C₂₂ H₃₁ O₆ PSi.C₁₂H₂₃ N: C,64.63; H,8.61; N,2.22 Found: C, 64.51; H, 8.49; N, 2.18

Example 8(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A. 2-Aminophenyl 4-fluorophenyl methanone

A dry 500 ml 3-neck flask fitted with a reflux condenser and an additionfunnel was charged with Mg turnings (2.80 gm, 0.115 mol) and dry Et₂ O(35 ml). A solution of 1-bromo- 4-fluorobenzene (18.5 gm, 0.106 mol) inEt₂ O (20 ml) was added to the addition funnel and approximately 15% ofthis solution was added to the Mg/Et₂ O mixture. Once the exothermicreaction had begun (ultrasound was required), the aryl bromide solutionwas added at such a rate as to maintain a gentle reflux. After theaddition was complete, the mixture was refluxed for an additional 30minutes, then cooled to 0° C. Dropwise addition of a solution of2-aminobenzonitrile (5.00 gm, 0.042 mol) in dry Et₂ O (20 ml) over a 10minute period resulted in the formation of a thick yellow slurry. Theresulting mixture was warmed to room temperature and stirred overnight.The solution was then cooled to 0° C. and cautiously quenched with 10%HCl (50 ml). After stirring for 5 minutes, the solution was made basicwith 10% NaOH (70 ml) and the aqueous layer was extracted three timeswith Et₂ O. The combined Et₂ O layers were pooled, washed with brine,dried (Na₂ SO₄), filtered and stripped to yield an orange oil. The oilwas chromatographed (Flash, Merck SiO₂, 25% EtOAc in hexane) to giveimpure 2-aminophenyl 4-fluorophenyl methanone (˜1 gm) and thecorresponding impure imine (˜5.8 gm, Rf 0.28 in 30% EtOAc in hexane).The imine was stirred with 10% HCl (100 ml) and silica gel (750 mg) for45 minutes. The mixture was then basicified with NaOH pellets (14 gm)and the aqueous layer was extracted twice with Et₂ O. The combined Et₂ Olayers were washed with brine, dried (Na₂ SO₄), filtered and stripped toyield a solid. This solid was pooled with impure 2-aminophenyl4-fluorophenyl methanone from above and recrystallized in hot EtOH/H₂ Oto give analytically pure 2-aminophenyl 4-fluorophenyl methanone asyellow crystals (3.28 gm, 36%).

m.p. 125.2°-127.4° C. TLC: R_(f) 0.41 (30% EtOAc in hexane)

B. 4-(Fluorophenyl)-2-(1-methylethyl)-3-quinolinecarboxylic acid, ethylester

A mixture of 2-aminophenyl 4-fluorophenyl methanone (3.051 gm, 14 mmol),ethyl isobutrylacetate (2.24 gm, 14 mmol) and concentrated H₂ SO₄ (0.14ml) in glacial HOAc (14 ml) was refluxed for 4 hours. The reactionmixture was cooled to room temperature and poured into an ice coldsolution of concentrated NH₄ OH (21 ml) in H₂ O (60 ml). The resultingmixture was extracted twice with Et₂ O and the combined Et₂ O extractswere washed with H₂ O and brine, then dried (Na₂ SO₄), filtered andstripped to yield an orange oil. Flash chromatography of the oil (MerckSiO₂, 10% EtOAc in hexane) afforded quinoline4-(Fluorophenyl)-2-(1-methylethyl)-3-quinolinecarboxylic acid, ethylester (3.212 gm, 68%) as a light yellow oil which slowly solidifiedovernight under vacuum.

m.p. 65.4°-69.0° C. TLC: R_(f) 0.46 (20% EtOAc in hexane)

C. 4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinemethanol

A solution of 4-(Fluorophenyl)-2-(1-methylethyl)-3-quinolinecarboxylicacid, ethyl ester (3.018 gm, 8.94 mmol) in Et₂ O (5 ml) was added to aslurry of LiAlH₄ (689 mg, 18.0 mmol) in Et₂ O (22 mol) at 0° C. After2.5 hours, the solution was quenched and diluted with H₂ O and theaqueous layer was extracted three times with Et₂ O. The combined Et₂ Oextracts were washed with brine, dried (Na₂ SO₄), filtered and stripped.The resulting oil was triturated with 30% EtOAc in hexane to obtain awhite solid. The solid was collected and the filtrate was concentratedand triturated with hexane to obtain additional solid. The pooled solidswere recrystallized from hot hexane/EtOAc to give analytically pure4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinemethanol as whitecrystals (1.516 gm). The mother liquor was stripped and recrystallizedagain from hot hexane/EtOAc, giving a total of 2.039 gm (77%)4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinemethanol.

m.p. 132.5°-134° C. TLC: R_(f) 0.22 (20% EtOAc in hexane)

D. 4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinecarboxaldehyde

Dess-Martin periodinane (1.018 gm, 2.40 mmol) was dissolved in dry CH₂Cl₂ (12 ml), treated with t-butanol (178 mg, 2.40 mmol) and theresulting mixture was stirred at room temperature for 15 minutes. Asolution of 4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinemethanol(539 mg, 1.82 mmol) in CH₂ Cl₂ (8 ml) was then added. After 25 minutes,the solution was then diluted with Et₂ O (40 ml) and 1N NaOH (25 ml),then stirred an additional 5 minutes. The phases were separated and theaqueous layer was extracted with Et₂ O. The combined organic layers werewashed with saturated NaHCO₃ and brine, then dried (Na₂ SO₄), filteredand stripped to give a yellow solid. Flash chromatography (Merck SiO₂,40% EtOAc in hexane) gave4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinecarboxaldehyde (491 mg,92%) as a white solid. Analytically pure material was obtained byrecrystallization from hot hexane.

m.p. 120.4°-122.2° C. TLC: R_(f) 0.47 (20% EtOAc in hexane)

E. 3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)quinoline

A solution of carbon tetrabromide (12.620 gm, 38.0 mmol) in CH₂ Cl₂ (20ml) was added over a 10 minute period to a cold (-10° C.) solution of4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinecarboxaldehyde (7.394gm, 25.2 mmol) and triphenylphosphine (19.86 gm, 75.7 mmol) in CH₂ Cl₂(140 ml). After the addition was complete, the mixture was stirred for20 minutes then quenched with saturated NaHCO₃ and extracted 2× with CH₂Cl₂. The combined organic layers were washed with brine, dried (Na₂SO₄), filtered and concentrated to 50 ml. The residue was trituratedwith Et₂ O and the precipitated triphenylphosphine oxide was removed byfiltration. The filtrate was stripped and the residue waschromatographed (flash, Merck SiO₂, 10% EtOAc in hexane) to give3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-2-(1 -methylethyl)quinoline asa light yellow foamy oil (11.556 gm, 102% theory).

TLC: R_(f) 0.50 (20% EtOAc in hexane)

F. 3-Ethynyl-4-(4-fluorophenyl)-2-(1-methylethyl)quinoline

A solution of3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)quinoline(25.2 mmol) in dry THF (140 ml) was cooled to -78° C. and treated withn-BuLi (1.6M in hexane, 33 ml, 52.8 mmol) over a 1 minute period. Afterstirring at -78° C. for one hour, the dark brown solution was quenchedwith saturated NH₄ Cl, warmed to room temperature, diluted with H₂ O,and extracted with Et₂ O. The Et₂ O extract was washed with brine, dried(Na₂ SO₄), filtered and stripped to give a yellow oil. The oil wasboiled in hot hexane and cooled (-15° C.) to afford3-Ethynyl-4-(4-fluorophenyl)-2-(1-methylethyl)-quinoline (5.198 gm) asyellow crystals. The mother liquor was stripped and chromatographed(flash, Merck SiO₂, 4% EtOAc in hexane) to afford additional productwhich was recrystallized from hot hexane. A total of 6.793 gm (93%) of3-Ethynyl-4-(4-fluorophenyl)-2-(1-methylethyl)quinoline was obtained.

TLC: R_(f) 0.49 (10% EtOAc in hexane)

G.(S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-[[[4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethynyl]methoxyphosphinyl]butanoicacid, methyl ester

(S)-4-(Hydroxymethoxyphosphinyl)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester, dicyclohexylamine (1:1) salt (4.501 gm, 7.123 mmol)(4.458 gm, 7.05 mmol) the preparation of which is described at the endof example 7, was partitioned between EtOAc and 5% KHSO₄), filtered andstripped to give a colorless oil (phosphinic acid monomethyl ester). Theoil was dissolved in dry CH₂ Cl₂ (15 ml) and treated withN,N-diethyltrimethylsilylamine (2.70 ml, 2.07 gm, 14.25 mmol). Afterstirring at room temperature for one hour, the solvent was removed invacuo and the residue was azeotroped with dry benzene (15 ml). Theresidue was dissolved in dry CH₂ Cl₂ (15 ml), cooled to -10° C. andtreated with 2 drops DMF and oxalyl chloride (677 ul). After 15 minutes,the solution was warmed to room temperature and stirred for anadditional 50 minutes. The solvent was then stripped and the yellowresidue (phosphinylchloridate) was azeotroped with benzene (15 ml) anddried in vacuo (oil pump) for 30 minutes.

Meanwhile, a solution of3-Ethynyl-4-(4-fluorophenyl)-2-(1-methylethyl)quinoline (1.200 gm, 4.15mmol) in THF (10 ml) at -78° C. was treated with n-BuLi (1.6M in hexane,2.85 ml, 4.56 mmol) and the resulting clear brown mixture was stirredfor 30 minutes. The acetylenic anion solution was added dropwise viacanula over a one minute period to a -78° C. solution of thephosphinylchloridate in THF (12 ml). The resulting yellow-brown mixturewas stirred at -78° C. for 30 minutes, then quenched with 50% saturatedNH₄ Cl. The solution was warmed to room temperature, diluted with H₂ O,and poured into saturated NaHCO₃. The aqueous phase was extracted 2×with Et₂ O. The combined Et₂ O layers were washed with brine, dried (Na₂SO₄), filtered and stripped. The residue was chromatographed (flash,Merck SiO₂, 40% EtOAc in hexane followed by 1:1 EtOAc:hexane) to afford(S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-[[[4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethynyl]methoxyphosphinyl]-butanoicacid, methyl ester as a colorless foam (1.800 gm, 60%).

TLC: R_(f) 0.24 (40% EtOAc in hexane)

H.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethynyl]-methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

A mixture of(S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-[[[4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethynyl]methoxyphosphinyl]butanoicacid, methyl ester (1.041 gm, 1.44 mmol), tetra-n-butylammonium fluoride(1.0M in THF, 5.7 ml, 5.7 mmol), and HOAc (525 mg, 8.73 mmol) in THF (14ml) was stirred at room temperature for 18 hours. The solution waspartitioned between 5% KHSO₄ and EtOAc. The layers were shaken andseparated and the EtOAc layer was washed again with 5% KHSO₄. The pooledaqueous washings were back-extracted twice with EtOAc. The combinedEtOAc layers were washed with brine and dried (Na₂ SO₄). Filtration andremoval the solvent afforded an oil. The oil was dissolved in cold (0°C.) 1:1 Et₂ O:MeOH and treated with excess diazomethane for 30 minutes.The excess diazomethane was destroyed by the addition of HOAc and thesolvent was removed in vacuo. The residue was chromatographed (flash,Merck SiO₂, 40% acetone in hexane followed by 1:1 actone:hexane) toafford(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethynyl]-methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester (612 mg, 91%) as an oil.

TLC: R_(f) 0.38 (1:1 acetone:hexane)

I.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A solution of(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethynyl]-methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester (285 mg, 0.59 mmol) in dioxane (4.0 ml) was treatedwith 1N LiOH (2.05 ml, 2.05 mmol) at room temperature and the mixturewas subsequently heated at 55° C. under argon for 1.5 hours. The solventwas evaporated and the residue was chromatographed on HP-20 eluting insuccession with H₂ O (200 ml), 25% MeOH in H₂ O (100 ml), and 50% MeOHin H₂ O (200 ml). The desired fractions were pooled and evaporated andthe residue was taken up in H₂ O and lyophilized to give(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methyl-ethyl)-3-quinolinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt (243 mg, 84%) as a white solid.

TLC: R_(f) 0.41 (7:2:1, i-PrOH, NH₄ OH, H₂ O)

Example 9(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, N-oxide, dilithium salt

A.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethynyl]-methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester. 1-oxide

A solution of(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethynyl]-methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester (332 mg, 0.67 mmol) (the preparation of which isdescribed in Example 8) and m-CPBA (80-85%, 585 mg) in dry CH₂ Cl₂ (18ml) was stirred at room temperature for 16 hours. Additional m-CPBA (277mg) was added and stirring was continued for 2 hours. The mixture wasdiluted with Et₂ O and washed with 50 ml saturated NaHCO₃ containing2.05 gm Na₂ SO₃. The organic layer was subsequently washed with brine,dried (Na₂ SO₄), filtered and stripped to yield an orange-brown residue.The residue was chromatographed (flash, Merck SiO₂, 40% hexane inacetone followed by 30% hexane in acetone) giving(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethynyl]-methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester. 1-oxide. (226 mg, 68%) as a viscous yellow oil.

TLC: R_(f) 0.18 (1:1 acetone:hexane)

B.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, N-oxide dilithium salt

A solution of(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethynyl]-methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester. 1-oxide. (220 mg, 0.44 mmol) in dioxane (3.0 ml) wastreated with 1N LiOH (1.9 ml, 1.9 mmol) at room temperature and themixture was subsequently heated at 55° C. under argon for 1 hour. Thesolvent was evaporated and the residue was chromatographed on HP-20eluting in succession with H₂ O (200 ml), 25% MeOH in H₂ O (100 ml), and50% MeOH in H₂ O (200 ml). The desired fractions were pooled andevaporated and the residue was taken up in H₂ O and lyophilized to give(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, N-oxide, dilithium salt (196 mg, 85%) as a dense yellow solid.

TLC: R_(f) 0.43 (7:2:1, i-PrOH, NH₄ OH, H₂ O)

Example 10

[3S,4(E)]-4-[[2-[2-(4-Fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A. (E)-2-(4-Fluorophenyl)-3-(2-iodoethenyl)-4-(1-methylethyl)quinoline

A mixture of 3-Ethynyl-2-(4-fluorophenyl)-4-(1-methylethyl)-quinoline(1.000 gm, 3.64 mmol) (the preparation of which is described in Example5) and AIBN (13 mg) in 140 ml of tri-n-butylstannyl hydride was rapidlyheated to 110° C. After 5 minutes of heating, the mixture was treatedwith additional Bu₃ SnH (0.4 ml) and the temperature of the reaction wasraised to 130° C. Approximately 10 mg of AIBN was added to the reactionmixture every 0.5 hours. After 4.5 hours, the mixture was cooled to roomtemperature, diluted with Et₂ O (25 ml) and treated with solid I₂ (3.08gm, 12.2 mmol). The dark reaction mixture was stirred for 1 hour, thenquenched with 10% Na₂ SO₃ in saturated NaHCO₃. The layers were shakenand separated. The ethereal layer was washed with brine, dried (Na₂SO₄), filtered and stripped to yield a yellow oil which was trituratedwith cold hexane to give a precipitate. Recrystallization of the solidfrom hot hexane gave 1.438 gm(E)-2-(4-Fluorophenyl)-3-(2-iodoethenyl)-4-(1-methylethyl)quinoline (917mg, 64%) as light yellow crystals.

m.p. 145°-147° C. TLC: R_(f) 0.15 (6% EtOAC in hexane)

B.(S,E)-3-[[(1,1-Dimethylethyl)diphenylsilyl]-4-[[2-[2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester

(S)-4-(Hydroxymethoxyphosphinyl)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester, dicyclohexylamine (1:1) salt (4.501 gm, 7.123 mmol)(1.548 gm, 2.45 mmol), the preparation of which is described at the endof example 7, was partitioned between EtOAc and 5% KHSO₄. The EtOAclayer was washed 3× with 5% KHSO₄, then with brine, then dried (Na₂SO₄), filtered and stripped to give a colorless oil (phosphinic acidmonomethyl ester). The oil was dissolved in dry CH₂ Cl₂ (10 ml) andtreated with N,N-diethyltrimethylsilylamine (930 ul, 713 gm, 4.91 mmol).After stirring at room temperature for one hour, the solvent was removedin vacuo and the residue was azeotroped with dry benzene (10 ml). Theresidue was dissolved in dry CH₂ Cl₂ (10 ml), cooled to -10° C. andtreated with 2 drops DMF and oxalyl chloride (235 ul). After 15 minutes,the solution was warmed to room temperature and stirred for anadditional 50 minutes. The solvent was then stripped and the yellowresidue (phosphinylchloridate) was azeotroped with benzene (20 ml) anddried in vacuo (oil pump) for 30 minutes.

Meanwhile, a solution of(E)-2-(4-Fluorophenyl)-3-(2-iodoethenyl)-4-(1-methylethyl)quinoline (600mg, 1.44 mmol) in THF (2 ml) was added over a 2 minute period to a -78°C. solution of t-butyllithium (1.7M in pentane, 1.78 ml, 3.03 mmol) inTHF (7 ml). The resulting green-brown solution was stirred for 20minutes then cooled to -100° C. The vinyl anion solution was added overa 30 second period to a -100° C. solution of the phosphinylchloridate inTHF (10 ml). The resulting orange mixture was stirred at -100° C. for 10minutes and at -78° C. for 20 minutes, then quenched with 50% saturatedNH₄ Cl. The solution was warmed to room temperature, diluted with H₂ O,poured into saturated NaHCO₃. The aqueous phase was extracted 2× withEt₂ O. The combined Et₂ O layers were washed with brine, dried (Na₂SO₄), filtered and stripped. The resulting yellow oil waschromatographed (flash, Merck SiO₂, 20% acetone in hexane followed by30% acetone in hexane) to afford(S,E)-3-[[(1,1-Dimethylethyl)diphenylsilyl]-4-[[2-[2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester as a white foam (561 mg, 54%).

TLC: R_(f) 0.31 (1:2 acetone:hexane)

C.(S,E)-4-[[2-[2-(4-Fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]-ethenyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

A solution of(S,E)-3-[[(1,1-Dimethylethyl)diphenylsilyl]-4-[[2-[2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester (542 mg, 0.749 mmol) in THF (10 ml) was treated withHOAc (215 ul, 226 mg, 3.76 mmol) and tetra-n-butylammonium fluoride(1.0M in THF, 2.25 ml, 2.25 mmol). After stirring at room temperaturefor 22 hours, the solution was poured into saturated NaHCO₃ andextracted with EtOAc. The EtOAc extract was washed with brine, dried(Na₂ SO₄), filtered and stripped to give an oil which was subsequentlychromatographed (flash, Merck, SiO₂, 1:1 acetone:hexane followed by 20%hexane in acetone).(S,E)-4-[[2-[2-(4-Fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]-ethenyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester (265 mg, 73%) was obtained as a white foam.

TLC: R_(f) 0.28 (1:1 acetone:hexane)

D.[3S,4(E)]-4-[[2-[2-(4-Fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A solution of(S,E)-4-[[2-[2-(4-Fluorophenyl)-4-(1-methyl-ethyl)-3-quinolinyl]-ethenyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester (255 mg, 0.525 mmol) in dioxane (3 ml) was treatedwith 1N LiOH (1.90 ml, 1.90 mmol) at room temperature and the mixturewas subsequently heated at 55° C. under argon for 1.25 hours. Thesolvent was evaporated and the residue was chromatographed on HP-20,eluting in succession with H₂ O (200 ml), 25% MeOH in H₂ O (100 ml), and50% MeOH in H₂ O (200 ml). The desired fractions were pooled andevaporated and the residue was taken up in H₂ O and lyophilized to give[3S,4(E)]-4-[[2-[2-(4-Fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethenyl]hydroxy-phosphinyl]-3-hydroxybutanoic acid, dilithium salt (232 mg, 89%)as a white solid.

TLC: R_(f) 0.40 (7:2:1, i-PrOH, NH₄ OH, H₂ O).

Example 11[3S,4(E)]-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethenyl]hydroxy-phosphinyl]-3-hydroxybutanoicacid, dilithium salt

a. (E)-4-(4-Fluorophenyl)-3-(2-iodoethenyl)-2-(1-methylethyl)quinoline

A mixture of 3-Ethynyl-4-(4-fluorophenyl)-2-(1-methylethyl)quinoline(1.500 gm, 5.18 mmol) (the preparation of which is described in Example8) and AIBN (15 mg) in tri-n-butylstannyl hydride (2.1 ml) was rapidlyheated to 120° C. After 3 minutes of heating, the mixture was treatedwith additional Bu₃ SnH (0.6 ml) and the temperature of the reaction wasraised to 130° C. Approximately 15 mg of AIBN was added to the reactionmixture of 0.5, 1, and 2 hours after heating was initiated. After 2.5hours, the mixture was cooled to room temperature, diluted with Et₂ O(30 ml) and treated with solid I₂ (3.86 gm, 15.2 mmol). The darkreaction mixture was stirred for 1 hour, then quenched with 10% Na₂ SO₃in saturated NaHCO₃. The layers were shaken and separated. The ethereallayer was washed with brine, dried (Na₂ SO₄), filtered and stripped toyield a liquid/solid residue. The residue was chromatographed (flash,Merck SiO₂, 4% EtOAc in hexane) to give slightly impure(E)-4-(4-Fluorophenyl)-3-(2-iodoethenyl)-2-(1-methylethyl)quinoline as asolid. Recrystallization of the solid from hot hexane gave(E)-4-(4-Fluorophenyl)-3-(2-iodoethenyl)-2-(1-methylethyl)quinoline(1.725 gm, 80%) as light yellow crystals.

m.p. 129.4°-131° C. TLC: R_(f) 0.22 (4% EtOAc in hexane)

B.(S,E)-3-[[(1,1-Dimethylethyl)diphenylsilyl]-oxy]-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester

(S)-4-(Hydroxymethoxyphosphinyl)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester, dicyclohexylamine (1:1) salt (4.501 gm, 7.123 mmol)(3.86 gm, 6.11 mmol) the preparation of which is described at the end ofexample 7, was partitioned between EtOAc and 5% KHSO₄. The EtOAc layerwas washed 3× with 5% KHSO₄ and then with brine, then dried (Na₂ SO₄),filtered and stripped to give a colorless oil (phosphinic acidmonomethyl ester). The oil was dissolved in dry CH₂ Cl₂ (15 ml) andtreated with N,N-diethyltrimethylsilylamine (2.32 ml, 1.78 gm, 12.2mmol). After stirring at room temperature for one hour, the solvent wasremoved in vacuo and the residue was azeotroped with dry benzene (20ml). The residue was dissolved in dry CH₂ Cl₂ (15 ml), cooled to -10° C.and treated with 2 drops DMF and oxalyl chloride (590 ul, 858 mg, 6.76mmol). After 15 minutes, the solution was warmed to room temperature andstirred for an additional 50 minutes. The solvent was then stripped andthe yellow residue (phosphinylchloridate) was azeotroped with benzene(20 ml) and dried in vacuo (oil pump) for 30 minutes.

Meanwhile, a solution of(E)-4-(4-Fluorophenyl)-3-(2-iodoethenyl)-2-(1-methylethyl)quinoline(1.500 mg, 3.59 mmol) in THF (3 ml) was added over a 3 minute period toa -78° C. solution of t-butyllithium (1.7M in pentane, 4.40 ml, 7.48mmol) in THF (10 ml). The resulting deep green solution was stirred for20 minutes then cooled to -100° C. The vinyl anion solution was addedover a one minute period to a -100° C. solution of thephosphinylchloridate in THF (15 ml). The resulting mixture was stirredat -100° C. for 10 minutes and at -78° C. for 20 minutes, then quenchedwith 50% saturated NH₄ Cl. The solution was warmed to room temperature,diluted with H₂ O, and poured into saturated NaHCO₃. The aqueous phasewas extracted 2× with Et₂ O. The combined Et₂ O layers were washed withbrine, dried (Na₂ SO₄), filtered and stripped. The resulting yellow oilwas chromatographed (flash, Merck SiO₂, 40% EtOAc in hexane followed by1:1 EtOAc:hexane) to afford(S,E)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester as an off-white foam (1.615 gm, 62%).

TLC: R_(f) 0.28 (1:1 EtOAc:hexane)

C.(S,E)-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]-ethenyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

A solution of(S,E)-3-[[(1,1-Dimethylethyl)diphenylsilyl]-oxy]-4-[[2-[4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester (1.136 gm, 1.57 mmol) in THF (14 ml) was treated withHOAc (450 ul, 472 mg, 7.9 mmol) and tetra-n-butylammonium fluoride (1.0Min THF, 5.40 ml, 5.40 mmol). After stirring at room temperature for 18hours, the solution was poured into saturated NaHCO₃ and extracted withEtOAc. The EtOAc extract was washed with brine, dried (Na₂ SO₄),filtered, and stripped to give an oil which was subsequentlychromatographed (flash, Merck SiO₂, 1:1 acetone:hexane).(S,E)-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]-ethenyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester (709 mg, 93%) was obtained as a colorless oil.

TLC: R_(f) 0.32 (1:1 acetone:hexane)

D.[3S,4(E)]-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A solution of(S,E)-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]-ethenyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester (240 mg, 0.496 mmol) in dioxane (3 ml) was treatedwith 1N LiOH (1.70 ml, 1.70 mmol) at room temperature and the mixturewas subsequently heated at 55° C. under argon for 1.5 hours., Thesolvent was evaporated and the residue was chromatographed on HP-20 onHP-20 eluting in succession with H₂ O (200 ml), 25% MeOH in H₂ O (100ml), and 50% MeOH in H₂ O (200 ml). The desired fractions were pooledand evaporated and the residue was taken up in H₂ O and lyophilized togive[3S,4(E)]-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt (210 mg, 86%) as a white solid.

TLC: R_(f) 0.36 (7:2:1, i-PrOH, NH₄ OH, H₂ O)

Example 12(S)-4-[[[2-(4-Fluorophenyl)-4-(1-methyl-ethyl)-3-quinolinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, 1-oxide, dilithium salt

A.(S)-4-[[[2-(4-Fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester. 1-oxide

A solution of(S)-4-[[[2-(4-Fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester (486 mg, 1.00 mmol) (the preparation of which isdescribed in Example 5) and m-CPBA (80-85%, 846 mg) in dry CH₂ Cl₂ (20ml) was stirred at room temperature for 15 hours. The mixture wasdiluted with Et₂ O and washed with 70 ml saturated NaHCO₃ containing 4.0gm Na₂ SO₃. The organic layer was subsequently washed with brine, dried(Na₂ SO₄), filtered and stripped to yield a yellow oil. The oil waschromatographed (flash, Merck SiO₂, 30% hexane in acetone) giving(S)-4-[[[2-(4-Fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester. 1-oxide (404 mg, 81%) as a light yellow oily foam.

TLC: R_(f) 0.15 (1:1 acetone:hexane)

B.(S)-4-[[[2-(4-Fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, 1-oxide, dilithium salt

A solution of(S)-4-[[[2-(4-Fluorophenyl)-4-(1-methylethyl)-3-quinolinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester. 1-oxide (395 mg, 0.79 mmol) in dioxane (5.0 ml) wastreated with 1N LiOH (3.0 ml, 3.0 mmol) at room temperature and themixture was subsequently heated at 55° C. under argon for 1.25 hours.The solvent was evaporated and the residue was chromatographed on HP-20eluting in succession with H₂ O (200 ml), 25% MeOH in H₂ O (100 ml), and50% MeOH in H₂ O (200 ml). The desired fractions were pooled andevaporated and the residue was taken up in H₂ O and lyophilized to give(S)-4-[[[2-(4-Fluorophenyl)-4-(1-methyl-ethyl)-3-quinolinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, 1-oxide, dilithium salt (333 mg, 81%) as a dense yellow solid.

TLC: R_(f) 0.33 (7:2:1, i-PrOH, NH₄ OH, H₂ O)

Example 13[3S,4(E)]-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, 1-oxide, dilithium salt

A.(S,E)-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethenyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester. 1-oxide

A solution of(S,E)-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethenyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester (438 mg, 0.906 mmol) (the preparation of which isdescribed in Example 11) and m-CPBA (80-85%, 755 mg) in dry CH₂ Cl₂ (16ml) was stirred at room temperature for 2 hours. Additional m-CPBA (285mg) was added and stirring was continued for another 2.5 hours. Themixture was diluted with EtOAc and washed with 75 ml saturated NaHCO₃containing 5.0 gm Na₂ SO₃. The organic layer was subsequently washedwith brine, dried (Na₂ SO₄), filtered and stripped to yield anorange-brown residue. The residue was chromatographed (flash, MerckSiO₂, 30% hexane in acetone followed by 100% acetone) giving(S,E)-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethenyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester. 1-oxide (298 mg, 66%) as a yellow gum.

TLC: R_(f) 0.12 (1:1 acetone:hexane)

B. [3S,4(E)]-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, 1-oxide, dilithium salt

A solution of(S,E)-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethenyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester. 1-oxide (282 mg, 0.56 mmol) in dioxane (4.0 ml) wastreated with 1N LiOH (1.8 ml, 1.8 mmol) at room temperature and themixture was subsequently heated at 55° C. under argon for 1.5 hours. Thesolvent was evaporated and the residue was chromatographed on HP-20eluting in succession with H₂ O (200 ml), 25% MeOH in H₂ O (100 ml), and50% MeOH in H₂ O (200 ml). The desired fractions were pooled andevaporated and the residue was taken up in H₂ O and lyophilized to give[3S,4(E)]-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, 1-oxide, dilithium salt (260 mg, 88%) as a dense pale yellowsolid.

TLC: R_(f) 0.37 (7:2:1, i-PrOH, NH₄ OH, H₂ O)

Example 14(S)-4-[[[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A.3-(2,2-Dibromoethenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenylpyridine

A solution of carbon tetrabromide (2.866 gm, 8.64 mmol) in CH₂ Cl₂ (8ml) was added over a 10 minute period to a cold (-10° C.) solution of2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde(1.840 gm, 5.76 mmol) (the preparation of which is described in Example3) and triphenylphosphine (4.590 gm, 17.5 mmol) in CH₂ Cl₂ (30 ml).After the addition was complete, the cooling bath was removed and themixture was stirred for 20 minutes. The solution was quenched withsaturated NaHCO₃ and extracted 2× with CH₂ Cl₂. The combined organiclayers were washed with saturated NaHCO₃, dried (Na₂ SO₄), filtered andconcentrated. The concentrate was chromatographed (flash, Merck, SiO₂,1:1 CH₂ Cl₂ : hexane) to give3-(2,2-Dibromoethenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenylpyridineas a white solid (2.701 gm, 99%).

m.p. 124°-126° C. TLC: R_(f) 0.28 (1:1 CH₂ Cl₂ :hexane)

B. 3-Ethynyl-2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenylpyridine

A solution of3-(2,2-Dibromoethenyl)-2-(4fluorophenyl)-4-(1-methylethyl)-6-phenylpyridine(2.677 gm, 5.63 mmol) in dry THF (25 ml) was cooled to -78° C. andtreated with n-BuLi (1.6M in hexane, 7.75 ml, 12.4 mmol) over a 1 minuteperiod. After stirring at -78° C. for one hours, the deep green solutionwas quenched with saturated NH₄ Cl, warmed to room temperature, dilutedwith H₂ O, and extracted once with Et₂ O. The Et₂ O extract was washedwith brine, dried (Na₂ SO₄), filtered and stripped to give a yellowsolid. The solid was recrystallized from a minimum amount of hot hexaneto afford analytically pure3-Ethynyl-2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenylpyridine asyellow crystals (1.572 gm, 89%).

m.p. 121°-123.5° C. TLC: R_(f) 0.33 (5% EtOAc in hexane)

C.(S)-3-[[1,1-Dimethylethyl)diphenylsilyl]oxy]-4-[[[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]-methoxyphosphinyl]butanoicacid, methyl ester

(S)-4-(Hydroxymethoxyphosphinyl)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester, dicyclohexylamine (1:1) salt (4.501 gm, 7.123 mmol)(2.018 gm, 3.19 mmol) the preparation of which is described at the endof example 7, was partitioned between EtOAc and 5% KHSO₄. The EtOAclayer was washed 3× with KHSO₄, then with brine, then dried (Na₂ SO₄),filtered and stripped to give a colorless oil (phosphinic acidmonomethyl ester). The oil was dissolved in dry CH₂ Cl₂ (10 ml) andtreated with N,N-diethyltrimethylsilylamine (1.22 ml, 0.94 gm, 6.44mmol). After stirring at room temperature for one hour, the solvent wasremoved in vacuo and the residue was azeotroped with dry benzene (10ml). The residue was redissolved in dry CH₂ Cl₂ (10 ml), cooled to -12°C. and treated with 2 drops DMF and oxalyl chloride (307 ul, 447 mg,3.52 mmol). After 15 minutes, the solution was warmed to roomtemperature and stirred for an additional 45 minutes. The solvent wasstripped and the yellow residue (phosphinylchloridate) was azeotropedwith benzene (20 ml) and dried in vacuo (oil pump) for 30 minutes.

Meanwhile, a solution of3-Ethynyl-2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenylpyridine (599 mg,1.9 mmol) in THF (8 ml) at -78° C. was treated with n-BuLi (1.6M inhexane, 1.30 ml, 2.08 mmol) and the resulting clear green mixture wasstirred for 30 minutes. The acetylenic anion solution was added dropwisevia canula over a 2 minute period to a -78° C. solution of thephosphinylchloridate in THF (12 ml). The resulting yellow-brown mixturewas stirred at -78° C. for 35 minutes, then quenched with 50% saturatedNH₄ Cl. The solution was warmed to room temperature, diluted with H₂ O,and poured into saturated NaHCO₃. The aqueous phase was extracted oncewith Et₂ O. The Et₂ O extract was washed with brine, dried (Na₂ SO₄),filtered and stripped. The residual oil was chromatographed (flash,Merck SiO₂, 1:1 EtOAc:hexane) to afford(S)-3-[[1,1-Dimethylethyl)diphenylsilyl]oxy]-4-[[[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]butanoicacid, methyl ester as a yellow-white foam (773 mg, 55%).

TLC: R_(f) 0.18 (40% EtOAc in hexane)

D.(S)-4-[[[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

A mixture of(S)-3-[[1,1-Dimethylethyl)diphenylsilyl]oxy]-4-[[[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]butanoicacid, methyl ester (750 mg, 1.00 mmol) tetra-n-butylammonium fluoride(1.0M in THF, 3.50 mmol), and HOAc (330 mg, 5.50 mmol) in THF (12 ml)was stirred at room temperature for 15 hours. The solution waspartitioned between 5% KHSO₄ and EtOAc. The layers were shaken andseparated and the EtOAc layer was washed again with 5% KHSO₄. The pooledaqueous washings were back-extracted twice with EtOAc. The combinedEtOAc layers were washed with brine and dried (Na₂ SO₄). Filtration andremoval the solvent afforded a yellow oil. The oil was dissolved in Et₂O and treated with excess diazomethane for 20 minutes. The excessdiazomethane was destroyed by the addition of HOAc and the solvent wasremoved in vacuo. The residue was chromatographed (flash, Merck SiO₂,40% acetone in hexane followed by 1:1 acetone:hexane) to afford(S)-4-[[[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester (446 mg, 88%) as a colorless oil.

TLC: R_(f) 0.34 (1:1 acetone:hexane)

E. (S)-4-[[[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoic acid,dilithium salt

A solution of(S)-4-[[[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester (436 mg, 0.86 mmol) in dioxane (5 ml) was treatedwith 1N LiOH (2.6 ml, 2.6 mmol) at room temperature and the mixture wassubsequently heated at 55° C. under argon for 1.5 hours. The solvent wasevaporated and the residue was chromatographed on HP-20 eluting insuccession with H₂ O (200 ml), 25% MeOH in H₂ O (100 ml), 50% MeOH in H₂O (250 ml). The desired fractions were pooled and evaporated and theresidue was taken up in H₂ O and lyophilized to give(S)-4-[[[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoic acid,dilithium salt (369 mg, 84%) as a white solid.

TLC: R_(f) 0.57 (7:2:1, i-PrOH, NH₄ OH, H₂ O)

Example 15[3S,4(E)]-4-[[2-[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A.(E)-2-(4-Fluorophenyl)-3-(2-iodoethenyl)-4-(1-methylethyl)-6-phenyl-pyridine

A mixture of3-Ethynyl-2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenylpyridine (700 mg,2.22 mmol) (the preparation of which is described in Example 14)and AIBN(11 mg) in tri-n-butylstannyl hydride (1.40 ml) was rapidly heated to120° C. After 5 minutes of heating, the temperature of the reaction wasraised to 140° C. and approximately 12 mg of AIBN was added to thereaction mixture every 0.5 hour thereafter. After 2.5 hours, the mixturewas cooled to room temperature, diluted with Et₂ O (20 ml) and treatedwith solid I₂ (2.00 gm, 7.9 mmol). The dark reaction mixture was stirredfor one hour, then quenched with 60 ml saturated NaHCO₃ containing 4 gmNa₂ SO₃. The layers were shaken and separated. The ethereal layer waswashed with brine, dried (Na₂ SO₄), filtered and stripped to yield ayellow oil. The oil was chromatographed twice (Merck SiO₂, 5 % EtOAc inhexane (1st) then 3% EtOAc in hexane (2nd)) to(E)-2-(4-Fluorophenyl)-3-(2-iodoethenyl)-4-(1-methylethyl)-6-phenyl-pyridine as a foam which solidified (671 mg).Recrystallization of the solid from hot hexane gave 482 mg of(E)-2-(4-Fluorophenyl)-3-(2-iodoethenyl)-4-(1-methylethyl)-6-phenyl-pyridine.An additional 100 mg of 2 was obtained from the mother liquor to give atotal of 582 mg (59%) product.

m.p. 110°-111° C. TLC: R_(f) 0.39 (10% EtOAC in hexane)

B.(S,E)-3-[[1,1-Dimethylethyl)diphenylsilyl]oxy]-4-[[2-[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester

(S)-4-(Hydroxymethoxyphosphinyl)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester, dicyclohexylamine (1:1) salt (4.501 gm, 7.123 mmol)(1.211 gm, 1.92 mmol) the preparation of which is described at the endof example 7, was partitioned between EtOAc and 5% KHSO₄. The EtOAclayer was washed 3× with 5% KHSO₄, then with brine, then dried (Na₂SO₄), filtered and stripped to give a colorless oil (phosphinic acidmonomethyl ester). The oil was dissolved in dry CH₂ Cl₂ (10 ml) andtreated with N,N-diethyltrimethylsilylamine (727 ul, 558 mg, 3.84 mmol).After stirring at room temperature for one hour, the solvent was removedin vacuo and the residue was azeotroped with dry benzene (10 ml). Theresidue was dissolved in dry CH₂ Cl₂ (10 ml) cooled to -10° C. andtreated with 2 drops DMF and oxalyl chloride (184 ul, 268 mg, 2.11mmol). After 15 minutes, the solution was warmed to room temperature andstirred for an additional 50 minutes. The solvent was then stripped andthe yellow residue (phosphinylchloridate) was azeotroped with benzene(10 ml) and dried in vacuo (oil pump) for 30 minutes.

Meanwhile, a solution of(E)-2-(4-Fluorophenyl)-3-(2-iodoethenyl)-4-(1-methylethyl)-6-phenyl-pyridine(502 mg, 1.13 mmol) in THF (2 ml) was added over a 2 minute period to a-78° C. solution of t-butyllithium (1.7M in pentane, 1.46 ml, 2.48 mmol)in THF (6 ml). The mixture was stirred for 20 minutes then cooled to-100° C. The vinyl anion solution was added over a one minute period toa -100° C. solution of the phosphinylchloridate in THF (10 ml). Theresulting mixture was stirred at -100° C. for 30 minutes and at -78° C.for 30 minutes, then quenched with 50% saturated NH₄ Cl. The solutionwas warmed to room temperature, diluted with H₂ O, and poured intosaturated NaHCO₃. The aqueous phase was extracted 2× with Et₂ O. Thecombined Et₂ O layers were washed with brine, dried (Na₂ SO₄), filteredand stripped. The resulting yellow oil was chromatographed (flash, MerckSiO₂, 15% acetone in hexane followed by 20% acetone in hexane) to afford(S,E)-3-[[1,1-Dimethylethyl)diphenylsilyl]oxy]-4-[[2-[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester as an off-white foam (256 mg, 30%).

TLC: R_(f) 0.29 (1:2 acetone:hexane)

C.(S,E)-4-[[2-[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester

A solution of(S,E)-3-[[1,1-Dimethylethyl)diphenylsilyl]oxy]-4-[[2-[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester (241 mg, 0.321 mmol) in THF (7 ml) was treated withHOAc (92 ul, 96 mg, 1.61 mmol) and tetra-n-butylammonium fluoride (1.0Min THF, 963 ul, 0.963 mmol). After stirring at room temperature for 18hours, the solution was poured into saturated NaHCO₃ and extracted withEtOAc. The EtOAc extract was washed with brine, dried, (Na₂ SO₄),filtered, and stripped to give an oil which was subsequentlychromatographed (flash, Merck SiO₂, 1:1 acetone:hexane followed 100%acetone).(S,E)-4-[[2-[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester (124 mg, 76%) was obtained as a colorless oil.

TLC: R_(f) 0.29 (1:1 acetone:hexane)

D.[3S,4(E)]-4-[[2-[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]-hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A solution of(S,E)-4-[[2-[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]butanoicacid, methyl ester (120 mg, 0.234 mmol) in dioxane (2 ml) was treatedwith 1N LiOH (0.9 ml, 0.9 mmol) at room temperature and the mixture wassubsequently heated at 55° C. under argon for 1.5 hours. The solvent wasevaporated and the residue was chromatographed on HP-20 eluting insuccession in H₂ O (150 ml), 25% MeOH in H₂ O (75 ml) and 50% MeOH in H₂O (200 ml). The desired fractions were pooled evaporated and the residuewas taken up in H₂ O and lyophilized to give[3S,4(E)]-4-[[2-[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt (108 mg, 86%) as a white solid.

TLC: R_(f) 0.52 (7:2:1, i-PrOH, NH₄ OH, H₂ O)

Examples 16 to 51

Following the procedures as outlined heretofore and as described in theprevious working examples, the following additional compounds may beprepared.

Examples of Structure 1 where Am=A₁, X=C.tbd.C

    ______________________________________                                         ##STR18##                     A1                                             Ex. #    Structure 1                                                          ______________________________________                                        16                                                                                      ##STR19##                                                           17                                                                                      ##STR20##                                                           18                                                                                      ##STR21##                                                           19                                                                                      ##STR22##                                                           20                                                                                      ##STR23##                                                           21                                                                                      ##STR24##                                                           ______________________________________                                    

Examples of Structure 1 where Am=A₁, X=C.tbd.C

    ______________________________________                                         ##STR25##                     A1                                             Ex. #    Structure 1                                                          ______________________________________                                        22                                                                                      ##STR26##                                                           23                                                                                      ##STR27##                                                           24                                                                                      ##STR28##                                                           25                                                                                      ##STR29##                                                           26                                                                                      ##STR30##                                                           27                                                                                      ##STR31##                                                           28                                                                                      ##STR32##                                                           29                                                                                      ##STR33##                                                           ______________________________________                                    

Examples of Structure 1 where Am=A₁, X=C.tbd.C

    ______________________________________                                         ##STR34##                     A1                                             Ex. #    Structure 1                                                          ______________________________________                                        30                                                                                      ##STR35##                                                           31                                                                                      ##STR36##                                                           32                                                                                      ##STR37##                                                           33                                                                                      ##STR38##                                                           34                                                                                      ##STR39##                                                           35                                                                                      ##STR40##                                                           36                                                                                      ##STR41##                                                           37                                                                                      ##STR42##                                                           ______________________________________                                    

Examples of Structure 1 where Am=A₁, X=C.tbd.C

    ______________________________________                                         ##STR43##                     A1                                             Ex. #    Structure 1                                                          ______________________________________                                        38                                                                                      ##STR44##                                                           39                                                                                      ##STR45##                                                           ______________________________________                                    

Examples of Structure 1 where Am=A₂, X=CH═CH(E)

    ______________________________________                                         ##STR46##                     A2                                             Ex. #    Structure 1                                                          ______________________________________                                        40                                                                                      ##STR47##                                                           41                                                                                      ##STR48##                                                           42                                                                                      ##STR49##                                                           43                                                                                      ##STR50##                                                           44                                                                                      ##STR51##                                                           45                                                                                      ##STR52##                                                           46                                                                                      ##STR53##                                                           47                                                                                      ##STR54##                                                           ______________________________________                                    

Examples of Structure 1 where Am=A₂, X=CH═CH(E)

    ______________________________________                                         ##STR55##                     A2                                             Ex. #    Structure 1                                                          ______________________________________                                        48                                                                                      ##STR56##                                                           49                                                                                      ##STR57##                                                           50                                                                                      ##STR58##                                                           51                                                                                      ##STR59##                                                           ______________________________________                                    

The following are the IUPAC names for the compounds described above:

16.(S)-4-[[[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt.

17.(S)-4-[[[4-Fluorophenyl)-2-(1-methylethyl)-5H-indeno[1,2-b]pyridin-3-yl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt.

18.(S)-4-[[[4-(4-Fluoro-3-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]-hydroxyphosphinyl-3-hydroxybutanoicacid, disodium salt.

19.(S)-4-[[[2-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt.

20.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-thienyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt.

21.(S)-4-[[[4-(4-Fluorophenyl)-5,6-dihydro-2-(1-methylethyl)benzo[h]quinolin-3-yl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt.

22.(S)-4-[[[6-(1,3-Benzodioxol-4-yl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt.

23.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-5,6-diphenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt.

24.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-methylphenyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt.

25.(S)-4-[[[6-[[1,1'-Biphenyl]-3-yl]-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt.

26.(S)-4-[[[6-(1,3-Benzodioxol-5-yl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt.

27.(S)-4-[[[2-(1,1-Dimethylethyl)-1-(4-fluoro-3-methylphenyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt.

28.(S)-4-[[[4-(4-Fluorophenyl)-6-methyl-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, 1-oxide, disodium salt.

29.(S)-4-[[[2-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-6-(2-methylphenyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt.

30.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, 1-oxide, disodium salt.

31.(S)-4-[[[4-(4-Fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-1-pyridin-3-yl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt.

32.(S)-4-[[[4-(4-Fluorophenyl)-5,6,7,8-tetrahydro-2-(1-methylethyl)-3-quinolinyl]-ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt.

33.(S)-4-[[[4-(4-Fluoro-3-methylphenyl)-2-(1-methylethyl)-3-quinolinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, 1-oxide, disodium salt.

34.(S)-4-[[[4-(1,1-Dimethylethyl)-2-(4-fluorophenyl)-3-quinolinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt.

35.(S)-4-[[[2-(4-Fluoro-3-methylphenyl)-4-(1-methylethyl)-3-quinolinyl]-ethynyl]hydroxyphosphinyl]-3-hyroxybutanoicacid, sodium salt.

36.(S)-4-[[[4-(3,5-Dimethylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt.

37.(S)-4-[[[4-Fluorophenyl)-2-(1-methylethyl)-6-(2-pyridinyl)-3-pyridinyl]ethnyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt.

38.(S)-4-[[[4-Fluorophenyl)-6-(2-hydroxyphenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt.

39.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-methylphenyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, 1-oxide, disodium salt.

40.(3R,5S,6E)-7-[4-(4-Fluoro-3-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, monosodium salt.

41.(3R,5S,6E)-7-[4-(3,5-Dimethylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, monosodium salt.

42.(3R,5S,6E)-7-[4-(4-Fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptanoicacid, monosodium salt.

43.(3R,5S,6E)-7-[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, monosodium salt.

44.(3R,5S,6E)-7-[2-(4-Fluoro-methylphenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, monosodium salt.

45.(3R,5S,6E)-7-[4-(4-Fluorophenyl)-2-(1-methylethyl)-5,6-diphenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, monosodium salt.

46.(3R,5S,6E)-7-[4-(4-Fluorophenyl)-2-(1-methylethyl)-5H-indeno[1,2-b]-pyridin-3-yl]-3,5-dihydroxy-6-heptenoicacid, monosodium salt.

47.(3R,5S,6E)-7-[4-(4-Fluorophenyl)-5,6-dihydro-2-(1-methylethyl)benzo-[h]quinolin-3-yl]-3,5-dihydroxy-6-heptenoicacid, monosodium salt.

48.(3R,5S,6E)-7-[2-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-6-phenyl-3-pyridinyl-3,5-dihydroxy-6-heptenoicacid, monosodium salt.

49.(3R,5S,6E)-7-[4-Fluoro-3-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, 1-oxide, monosodium salt.

50.(3R,5S,6E)-7-[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, 1-oxide, monosodium salt.

51.(3R,5S,6E)-7-[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-methylphenyl)-3-pyridinyl-3,5-dihydroxy-6-heptenoicacid, 1-oxide, monosodium salt.

Example 52(S)-4-[[[4-(4-Fluoro-3-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A. 4-Fluoro-2-methylbenzaldehyde

A -78° C. solution of 2-fluoro-5-bromotoluene (25.764 gm, 136.3 mmol) inTHF (200 ml) was treated with n-BuLi (2.5M in hexane, 60 ml, 150 mmol)over a 12-minute period. After stirring for one hour, the cloudy whitemixture was treated with neat dimethylformamide (30 ml, 28.3 gm, 387mmol) over a two-minute period. Stirring continued for an additionalhour. The mixture was then quenched with saturated NH₄ Cl, warmed toroom temperature, and made acidic with 10% HCl. The mixture wasextracted with Et₂ O and the ether extract was washed with H₂ O andbrine, then dried (Na₂ SO₄), filtered, and stripped. The dark residuewas distilled (bp 55° C. @1 mm) to give the title compound (16.286 gm,86%).

TLC: R_(f) 0.28 (20% EtOAc in hexane)

B. 3-(4-Fluoro-2-methylphenyl)-1-phenyl-2-propen-1-one

A mixture of the compound from part A (16.000 gm, 115.8 mmol) andacetophenone (13.920 gm, 115.8 mmol) in absolute EtOH (120 ml) wastreated with a solution of EtONa in EtOH (21% solution, 4.3 ml, 11.6mmol). A precipitate soon fell out of solution. After stirring at roomtemperature for 16 hours, the mixture was cooled to -10° C. and theprecipitate was collected by filtration. The solid was washed with coldEtOH and dried in vacuo to yield the part B compound (23.560 gm, 85%) asa light yellow solid.

m.p. 100°-101° C. TLC: R_(f) 0.42 (20% EtOAc in hexane) Anal. Calc'd forC₁₆ H₁₃ FO: C 79.98 H 5.45 F 7.91 Found: C 79.80 H 5.35 F 8.03

C.β-(4-Fluoro-2-methylphenyl)-α-(2-methyl-1-oxopropyl)-Δ-oxobenzenepentanoicacid, ethyl ester

A slurry of the part B compound (23.165 gm, 96.4 mmol) and ethylisobutyrylacetate (22.88 gm, 144.6 mmol) in absolute EtOH (400 ml) wastreated with a solution of EtONa in EtOH (21% by weight solution, 5.4ml, 14.5 mmol). After stirring at room temperature for 4.5 hours, thesolution was concentrated to 200 ml and partitioned between 50%saturated NH₄ Cl and EtOAc. The layers were separated and the EtOAclayer was washed with H₂ O (2×) and brine (2×), then dried (Na₂ SO₄),filtered and stripped to yield an oil. The oil was taken up in hexaneand cooled to produce a solid. The mixture was boiled and cooled to givethe title compound a mixture of diastereomers, as a white amorphoussolid (30.815 gm, 80%).

TLC: R_(f) 0.34 and 0.30 (20% EtOAc in hexane)

D.4-(4-Fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxylicacid, ethyl ester

A mixture of part C compound (30.395 gm, 76.3 mmol), NH₄ OAc (17.70 gm,229.6 mmol), and Cu(OAc)₂ (38.062 gm, 190.6 mmol) in glacial HOAc (200ml) was gently refluxed for three hours. The solution was cooled to roomtemperature and subsequently poured into an ice cold mixture ofconcentrated NH₄ OH (240 ml) in H₂ O (320 ml). The mixture was extractedwith Et₂ O and the Et₂ O extract was washed with H₂ O (2×) and brine,then dried (Na₂ SO₄), filtered and stripped to yield the title compoundas a crude yellow oil (28.460 gm, 99%). The crude material was useddirectly for the next reaction.

TLC: R_(f) 0.51 (20% EtOAc in hexane)

E.4-(4-Fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinemethanol

A cold (0° C.) solution of the crude part D compound (28.46 gm) in dryTHF (350 ml) was treated with LiAlH₄ (9.20 gm, 242 mmol). Ten minutesafter the addition, the cooling bath was removed and the mixture wasstirred at room temperature for two hours. The dark solution wasrecooled to 0° C. and quenched with enough H₂ O to form a thick aluminumsalt paste. The solution was filtered and the salts were washed withEtOAc. The filtrate was washed with H₂ O and brine, then dried (Na₂SO₄). Filtration and removal of the solvent afforded a solid. The solidwas recrystallized from hot EtOAc/hexane to provide the title compound(19.152 gm, 75% from the part C compound) as a white solid.

m.p. 159°-160° C. TLC: R_(f) 0.30 (20% EtOAc in hexane) Anal Calc'd forC₂₂ H₂₂ FNO: C 78.78 H 6.61 N 4.18 F 5.66 Found: C 78.65 H 6.71 N 4.01 F5.67

F.4-(4-Fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde

A -78° C. solution of oxalyl chloride (1.30 ml, 1.89 gm, 14.9 mmol) inCH₂ Cl₂ (80 ml) was treated dropwise with a solution of dry DMSO (2.05ml, 2.26 gm, 29 mmol) in CH₂ Cl₂ (2 ml). After 15 minutes, a solution ofthe alcohol prepared in part E (4.000 gm, 11.93 mmol) in CH₂ Cl₂ (13 ml)and THF (5 ml) was added dropwise to the above mixture. Twenty minutesafter the addition, TEA (8.3 ml) was added and the mixture was stirredat -78° C. for 10 minutes and then warmed to room temperature. Themixture was diluted with Et₂ O and washed twice with H₂ O and once withbrine. The organic layer was dried (Na₂ SO₄), filtered, and stripped toyield a yellow solid. Recrystallization of the solid from hot hexaneafforded the title compound as hard colorless crystals (3.684 gm, 93%).

m.p. 110.5°-112.5° C. TLC: R_(f) 0.53 (20% EtOAc in hexane) Anal Calc'dfor C₂₂ H₂₀ FNO: C 79.26 H 6.05 N 4.20 F 5.70 Found: C 79.10 H 5.98 N4.11 F 5.58

G.3-(2,2-Dibromoethenyl)-4-(4-fluoro-2-methylphenyl)-2-(1-methylethyl-6-phenylpyridine

A solution of carbon tetrabromide (5.39 gm, 16.3 mmol) in CH₂ Cl₂ (15ml) was added over a 5-minute period to a cold (0° C.) solution of thealdehyde prepared in part F (3.610 gm, 10.83 mmol) andtriphenylphosphine (8.52 gm, 32.5 mmol) in CH₂ Cl₂ (60 ml). After theaddition was complete, the mixture was stirred at 0° C. for 20 minutesand then at room temperature for 10 minutes. The solution was quenchedwith saturated NaHCO₃ and extracted twice with CH₂ Cl₂. The combinedorganic layers were dried (Na₂ SO₄), filtered and concentrated. Theconcentrate was chromatographed (flash, Merck SiO₂, 30% CH₂ Cl₂ inhexane) to give the title compound (5.076 gm, 96%) as a colorless oilwhich slowly solidified on standing.

m.p. 102.5°-104.5° C. TLC: R_(f) 0.58 (20% EtOAc in hexane)

H.(S)-4-[[[4-(4-Fluoro-3-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

Meanwhile, a solution of the dibromide prepared in part G (3.000 gm,6.13 mmol) in THF (15 ml) at -78° C. was treated with n-BuLi (2.5M inhexane, 4.9 ml, 12.25 mmol) over a 1-minute period and the resultingclear green-brown solution was stirred for 1 hour. The acetylenic anionsolution was added dropwise via cannula over a 5-minute period to a -78°C. solution of the phosphonochloridate from Example 57, part G, in THF(20 ml). The resulting yellow-brown mixture was stirred at -78° C. for30 minutes, then quenched with 75% saturated NH₄ Cl. The solution waswarmed to 0 ° C., diluted with H₂ O, and poured into saturated NaHCO₃.The aqueous phase was extracted once with Et₂ O. The Et₂ O layer waswashed with brine, dried (Na₂ SO₄), filtered and stripped to give anorange oil. The residue was chromatographed (flash, Merck SiO₂, 40%EtOAc in hexane) to afford the title compound as a pale yellow foam(3.515 gm, 75%).

TLC: R_(f) 0.31 (40% EtOAc in hexane)

I.(S)-4-[[[4-(4-Fluoro-3-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

A mixture of compound H (3.480 gm, 4.55 mmol), tetra-n-butylammoniumfluoride (1.0M in THF, 13.6 ml, 13.6 mmol), and HOAc (1.31 ml, 1.37 gm,22.9 mmol) in THF (25 ml) was stirred at room temperature for 16 hours.The solution was diluted with EtOAc and washed three times with 5%KHSO₄. The aqueous layers were back-extracted twice with EtOAc and thepooled EtOAc layers were dried (Na₂ SO₄), filtered and stripped toafford a yellow oil. The oil was dissolved in Et₂ O, cooled to 0° C. andtreated with excess diazomethane for 20 minutes. The excess diazomethanewas destroyed by the addition of HOAc and the solvent was removed invacuo. The residue was chromatographed (flash, Merck SiO₂, 40% acetonein hexane followed by 1:1 acetone:hexane) to afford the title compound(1.949 gm, 82%) as a colorless oil.

TLC: R_(f) 0.33 (1:1--acetone:hexane)

J.(S)-4-[[[4-(4-Fluoro-3-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A solution of the compound (500 mg, 0.955 mmol) in dioxane (5 ml) wastreated with 1N LiOH (3.3 ml, 3.3 mmol) at room temperature and themixture was subsequently heated at 55° C. under argon for 1.5 hours. Thesolvent was evaporated and the residue was chromatographed on HP-20eluting in succession with H₂ O (200 ml), 25% MeOH in H₂ O (100 ml), 50%MeOH in H₂ O (200 ml), and 100% MeOH (100 ml). The desired fractionswere pooled and evaporated and the residue was taken up in H₂ O andlyophilized to give Example 52 (431 mg, 86%) as a white solid.

TLC: R_(f) 0.45 (7:2:1--i-propanol:NH₄ OH:H₂ O) Anal Calc'd for C₂₇ H₂₅FLi₂ NO₅ P * 1.11 H₂ O: C 61.48 H 5.20 N 2.66 F 3.60 P 5.87 Found: C61.51 H 5.31 N 2.63 F 3.78 P 5.85

Example 53(S)-4-[[[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A. 2-[(4-Fluorophenyl)methylene]-4-methyl-3-oxopentanoic acid, ethylester

A mixture of 4-fluorobenzaldehyde (3.00 gm, 24 mmol), ethylisobutyrylacetate (3.82 gm, 24 mmol), piperdine (240 ul), and HOAc (42ul) was refluxed in benzene (15 ml) with removal of water (Dean-Starktrap) for 22 hours. The cooled mixture was diluted with Et₂ O and washedsuccessively with 2% HCl, saturated NaHCO₃, H₂ O, and brine, then dried(Na₂ SO₄), filtered, and stripped to yield an oil. Distillation of theoil (bp 110°-113° C. at 0.25 mm) afforded the title compound (5.32 gm,83%) as a pale yellow liquid. This reaction has been successfully scaledup to 300 mmol.

TLC: R_(f) 0.35 (20% EtOAc in hexane) Micro Analyzed for C₁₅ H₁₇ FO₃ :Calc'd: C 68.17 H 6.48 F 7.19 Found: C 68.06 H 6.65 F 7.35

B. β-(4-Fluorophenyl)-α-(2-methyl-1-oxopropyl)-Δoxobenzenepentanoicacid, ethyl ester

A -78° C. solution of LiN(TMS)₂ (1.0M in THF, 14.1 ml, 14.1 mmol) in dryTHF (15 ml) was treated with a solution of propiophenone (1.900 gm, 14.2mmol) in THF (1.5 ml) over a 5-minute period. After one hour, a solutionof the part A compound (3.717 gm, 14.1 mmol) in THF (3 ml) was addeddropwise to the above solution. After 1.5 hours, the mixture wasquenched with saturated NH₄ Cl and warmed to room temperature. Themixture was diluted with H₂ O and subsequently extracted twice with Et₂O. The combined Et₂ O extracts were washed with brine, dried (Na₂ SO₄),filtered, and stripped to give an oil. Flash chromatography (Merck SiO₂,15% EtOAc in hexane) afforded the title compound (4.755 gm, 85%) as amixture of diastereomers.

TLC: R_(f) 0.34 & 0.31 (20% EtOAc in hexane)

C.4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxylicacid, ethyl ester

A mixture of the part B compound (4.730 gm, 11.87 mmol), NH₄ OAc (2.745gm, 35.6 mmol), and Cu(OAc)₂ (5.935 gm, 29.7 mmol) in glacial HOAc (30ml) was gently refluxed for 24 hours. The solution was cooled to roomtemperature and subsequently poured into an ice cold mixture ofconcentrated NH₄ OH (50 ml) in H₂ O (100 ml). The mixture was extractedtwice with Et₂ O and the pooled Et₂ O extracts were washed with H₂ O andbrine, then dried (Na₂ SO₄), filtered and stripped to yield an oil. Theoil was flashed (Merck SiO₂, 20% EtOAc in hexane) to give the title 3 asan oil (3.916 gm, 87%), which slowly solidified on standing.

m.p. 84°-88° C. TLC: R_(f) 0.47 (20% EtOAc in hexane)

D. 4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinemethanol

A cold (0° C.) solution of the ester from part C (4.571 gm, 12.11 mmol)in dry THF (60 ml) was treated with LiAlH₄ (1.49 gm, 39.3 mmol). Tenminutes after the addition, the cooling bath was removed and the mixturewas stirred at room temperature for 4 hours. An additional 500 mg ofLiAlH₄ was added and stirring was continued for two more hours. Thesolution was recooled to 0° C. and quenched in succession with H₂ O (2ml), 10% NaOH (2.5 ml), and H₂ O (6 ml). The solution was filtered andthe salts were washed with EtOAc. The filtrate was washed with H₂ O andbrine, then dried (Na₂ SO₄). Filtration and removal of the solventafforded a solid. The solid was recrystallized from hot EtOAc/hexane toprovide the title compound (3.729 gm, 92%) as white crystals.

m.p. 182°-184° C. TLC: R_(f) 0.20 (20% EtOAc in hexane) Microanalysisfor C₂₂ H₂₂ FNO: Calc'd: C 78.78 H 6.61 N 4.18 F 5.66 Found: C 78.76 H6.44 N 4.15 F 5.53

E. 4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde

A -78° C. solution of oxalyl chloride (1.20 ml, 1.75 gm, 13.7 mmol) inCH₂ Cl₂ (60 ml) was treated dropwise with a solution of dry DMSO (2.20ml, 2.42 gm, 31 mmol) in CH₂ Cl₂ (2 ml). After 15 minutes, a solution ofthe alcohol from part D (3.625 gm, 10.81 mmol) in CH₂ Cl₂ (10 ml) andTHF (10 ml) was added dropwise to the above mixture. Twenty-five minutesafter the addition, TEA (8.5 ml) was added and the mixture was stirredat -78° C. for 10 minutes and then warmed to room temperature. Themixture was diluted with Et₂ O and washed twice with H₂ O and once withbrine. The organic layer was dried (Na₂ SO₄), filtered, and stripped.The residue was triturated with Et₂ O to give a solid/liquid mixture.The mixture was taken up in hot hexane and cooled to give the aldehydetitle compound (3.282 gm, 91%) as white needles.

m.p. 111°-112° C. TLC: R_(f) 0.51 (20% EtOAc in hexane) Microanalysisfor C₂₂ H₂₀ FNO: Calc'd: C 79.25 H 6.05 N 4.20 F 5.70 Found: C 79.28 H6.10 N 4.13 F 5.63

F.3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenylpyridine

A solution of carbon tetrabromide (4.785 gm, 14.4 mmol) in CH₂ Cl₂ (10ml) was added over a 8-minute period to a cold (0° C.) solution of thealdehyde from part E (3.174 gm, 9.52 mmol) and triphenylphosphine (7.556gm,, 28.8 mmol) in CH₂ Cl₂ (60 ml). After the addition was complete, thecooling bath was removed and the mixture was stirred for 20 minutes. Thesolution was quenched with saturated NaHCO₃ and extracted twice with CH₂Cl₂. The combined organic layers were dried (Na₂ SO₄), filtered andconcentrated. The concentrate was chromatographed (flash, Merck SiO₂,30% CH₂ Cl₂ in hexane) to give the dibromide title compound as a whitesolid. The solid was recrystallized from hot hexane to give the product(4.345 gm, 93%) as white crystals.

m.p. 169°-170° C. TLC: R_(f) 0.58 (20% EtOAc in hexane) Microanalysisfor C₂₃ H₂₀ Br₂ FN: Calc'd: C 56.47 H 4.12 N 2.86 F 3.88 Br 32.67 Found:C 56.54 H 4.18 N 2.79 F 3.71 Br 32.22

G.(S)-4-[[[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

A solution of the dibromide from part F (2.000 gm, 4.09 mmol) in THF (10ml) at -78° C. was treated with n-BuLi (2.5M in hexane, 3.3 ml, 8.25mmol) over a 1.5-minute period and the resulting clear yellow solutionwas stirred for 1 hour. The acetylenic anion solution was added dropwisevia cannula over a 5-minute period to a -78° C. solution of thephosphonochloridate prepared in Example 57, part G in THF (14 ml). Theresulting mixture was stirred at -78° C. for 30 minutes, then quenchedwith 50% saturated NH₄ Cl. The solution was warmed to 0° C., dilutedwith H₂ O, and poured into saturated NaHCO₃. The aqueous phase wasextracted once with Et₂ O. The Et₂ O layer was washed with brine, dried(Na₂ SO₄), filtered and stripped to give an orange oil. The residue waschromatographed (flash, Merck SiO₂, 40% EtOAc in hexane followed by 1:1EtOAc:hexane) to afford the title compound as a colorless foam (2.169gm, 69%).

TLC: R_(f) 0.24 (40% EtOAc in hexane)

H.(S)-4-[[[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester

A mixture of the part G compound (2.136 gm, 2.80 mmol),tetra-n-butylammonium fluoride (1.0M in THF, 8.4 ml, 8.4 mmol), and HOAc(800 ul, 839 mg, 14 mmol) in THF (15 ml) was stirred at room temperaturefor 18 hours. The solution was diluted with EtOAc and washed three timeswith 5% KHSO₄. The aqueous layers were back-extracted once with EtOAcand the pooled EtOAc layers were dried (Na₂ SO₄), filtered and strippedto afford a yellow oil. The oil was dissolved in Et₂ O, cooled to 0° C.and treated with excess diazomethane for 20 minutes. The excessdiazomethane was destroyed by the addition of HOAc and the solvent wasremoved in vacuo. The residue was chromatographed (flash, Merck SiO₂,40% acetone in hexane followed by 1:1 acetone:hexane) to afford thetitle compound (1.200 gm, 82%) as a colorless oil.

TLC: R_(f) 0.34 (1:1--acetone:hexane)

I.(S)-4-[[[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A solution of the title compound (482 mg, 0.92 mmol) in dioxane (5 ml)was treated with 1N LiOH (3.2 ml, 3.2 mmol) at room temperature and themixture was subsequently heated at 55° C. under argon for 1.5 hours. Thesolvent was evaporated and the residue was chromatographed on HP-20,eluting in succession with H₂ O (200 ml), 25% MeOH in H₂ O (100 ml), and50% MeOH in H₂ O (200 ml). The desired fractions were pooled andevaporated and the residue was taken up in H₂ O and lyophilized to giveExample 53 (392 mg, 81%) as a white solid.

TLC: R_(f) 0.50 (7:2:1--i-propanol:NH₄ OH:H₂ O) Anal. Calc'd for C₂₇ H₂₅FLi₂ NO₅ P * 1.06 H₂ O: C 61.59 H 5.19 N 2.66 F 3.61 P 5.88 Found: C61.54 H 5.40 N 2.71 F 3.65 P 5.92

Example 54(S)-4-[[[2-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A. 3-(4-Fluorophenyl)-1-phenyl-2-propen-1-one

A mixture of acetophenone (7.02 gm, 58.4 mmol), p-fluorobenzaldehyde(7.24 gm, 58.4 mmol) and concentrated H₂ SO₄ (10 ml) in glacial HOAc(116 ml) was stirred at room temperature for 2 days. The solution waspoured into H₂ O (250 ml) and neutralized with 10% NaOH (200 ml). Theaqueous layer was extracted once with Et₂ O and the Et₂ O layer waswashed successively with H₂ O, saturated NaHCO₃ (twice) and brine, thendried (magnesium sulfate). Filtration and removal of the solventafforded a yellow solid, which was recrystallized from hot hexane togive the title compound (7.94 gm, 60%) as light yellow needles.

m.p. 86°-88° C. TLC: R_(f) =0.36 (20% EtOAc in hexane) Anal. Calc'd forC₁₅ H₁₁ FO: C 79.63 H 4.90 F 8.40 Found: C 79.76 H 4.95 F 8.50

B. β-(4-Fluorophenyl-α-(2,2-dimethyl-1-oxopropyl)-Δ-oxobenzenepentanoicacid, ethyl ester

A mixture of compound A (5.157 gm, 22.8 mmol) and ethyl pivaloylacetate(5.100 gm, 29.6 mmol) in absolute EtOH (100 ml) was treated with asolution of EtONa in EtOH (21% by weight solution, 1.28 ml, 3.4 mmol).After stirring at room temperature for 22 hours, a thick precipitate hadformed. The mixture was diluted with EtOAc and poured into 50% saturatedNH₄ Cl. The EtOAc layer was washed with H₂ O twice and brine, then dried(Na₂ SO₄), filtered and stripped to yield a solid. The solid wasrecrystallized from hot EtOAc/hexane to afford the title compound, amixture of diastereomers, as a white amorphous solid (8.673 gm, 95%).

TLC: R_(f) 0.26 and 0.23 (20% EtOAc in hexane)

C.2-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-6-phenyl-3-pyridinecarboxylicacid, ethyl ester

A mixture of the compound of part B (8.440 gm, 21.2 mmol), NH₄ OAc (4.92gm, 63.8 mmol), and Cu(OAc)₂ (10.50 gm, 52.6 mmol) in glacial HOAc (55ml) was gently refluxed for six hours. The solution was cooled to roomtemperature and subsequently poured into an ice cold mixture ofconcentrated NH₄ OH (91 ml) in H₂ O (180 ml). The mixture was extractedwith Et₂ O and the Et₂ O extract was washed with H₂ O and brine, thendried (Na₂ SO₄), filtered and stripped to yield a dark red oil. The oilwas flashed (Merck SiO₂, 5% EtOAc in hexane) to afford ester C (5.347gm, 67%) as a red oil which slowly solidified on standing.

TLC: R_(f) 0.55 (20% EtOAc in hexane)

D. 2-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-6-phenyl-3-pyridine methanol

A solution of the ester prepared in part C (5.319 gm, 14.1 mmol) in THF(100 ml) was treated with LiAlH₄ (2.58 gm, 68 mmol) and subsequentlystirred at room temperature for two days. TLC analysis showedessentially no reaction. The mixture was refluxed for 9 hours and thenstirred at room temperature for an additional 13 hours. The cooled (0°C.) reaction mixture was quenched successively with H₂ O (2.6 ml), 10%NaOH (2.6 ml), and H₂ O (8 ml). The solids were removed by filtrationand the aluminum salts were washed with EtOAc. The filtrate was strippedand the resulting orange oil was flashed (Merck SiO₂, 20% EtOAc inhexane) to obtain a mixture of pure and impure product. The impurefractions were rechromatographed (Merck SiO₂, 20% EtOAc in hexane) andthe pure fractions were pooled with the above to yield the titlecompound (1.478 gm, 31%) as a yellow oily foam.

TLC: R_(f) 0.40 (20% EtOAc in hexane)

E. 2-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-6-phenyl-3-pyridinecarboxaldehyde

A -78° C. solution of oxalyl chloride (580 ul, 844 mg, 6.65 mmol) in CH₂Cl₂ (23 ml) was treated dropwise with a solution of dry DMSO (950 ul,1.05 gm, 13.4 mmol) in CH₂ Cl₂ (1.5 ml). After 20 minutes, a solution ofalcohol D (1.459 gm, 4.35 mmol) in CH₂ Cl₂ (4 ml) was addded dropwise tothe above mixture. Thirty minutes after the addition, TEA (4.0 ml) wasadded and the mixture was stirred at -78° C. for 15 minutes and thenwarmed to room temperature. The mixture was diluted with Et₂ O andwashed twice with H₂ O and once with brine. The organic layer was dried(Na₂ SO₄), filtered, and stripped to yield an oil. The oil was purifiedby flash chromatography (Merck SiO₂, 5% EtOAc in hexane) to giveslightly impure aldehyde (title compound) as an oil which solidified onstanding. Recrystallization of the solid from hot hexane afforded thetitle compound as a pale yellow solid (1.125 gm, 78%).

m.p. 101°-102° C. TLC: R_(f) 0.52 (20% EtOAc in hexane) Microanalysisfor C₂₂ H₂₀ FNO: Calc'd: C 79.25 H 6.05 N 4.20 F 5.70 Found: C 78.99 H6.13 N 4.27 F 5.77

F.3-(2,2-Dibromoethenyl)-2-(1,1-dimethylethyl)-4-(4-fluorophenyl)-6-phenylpyridine

A cold (-7° C.) solution of the aldehyde from part E (729 mg, 2.19 mmol)and triphenylphosphine (2.248 gm, 8.6 mmol) in CH₃ CN (15 ml) and CH₂Cl₂ (4 ml) was treated with a solution of CBr₄ (1.632 gm, 4.92 mmol) inCH₃ CN (4 ml) over a 10-minute period. The cooling was removed and themixture was stirred at room temperature for 24 hours. The solution wasquenched with saturated NaHCO₃ and extracted twice with CH₂ Cl₂. Thecombined organic layers were dried (Na₂ SO₄), filtered and concentrated.The concentrate was chromatographed (flash, Merck SiO₂, 20% CH₂ Cl₂ inhexane) to give the dibromide (title compound) (810 mg, 75%) as acolorless oil.

TLC: R_(f) 0.53 (10% EtOAc in hexane)

G.(S)-4-[[[2-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

A solution of the dibromide of part F (1.262 gm, 2.58 mmol) in THF (8ml) at -78° C. was treated with n-BuLi (2.5M in hexane, 2.2 ml, 5.5mmol) over a 1-minute period and the resulting dark blue-green solutionwas stirred for 1 hour. The acetylenic anion solution was added dropwisevia cannula over a 4-minute period to a -78° C. solution of thephosphonochloridate of Example 57, part G, in THF (12 ml). The resultingmixture was stirred at -78° C. for 45 minutes, then quenched with 50%saturated NH₄ Cl. The solution was warmed to room temperature, dilutedwith H₂ O, and poured into saturated NaHCO₃. The aqueous phase wasextracted once with Et₂ O. The Et₂ O layer was washed with brine, dried(Na₂ SO₄), filtered and stripped to give an orange oil. The residue waschromatographed (flash, Merck SiO₂, 40% EtOAc in hexane) to afford thetitle compound as an off-white foam (698 mg, 35%).

TLC: R_(f) 0.30 (40% EtOAc in hexane)

H.(S)-4-[[[2-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester

A mixture of the compound of part G (689 mg, 0.902 mmol),tetra-n-butylammonium fluoride (1.0M in THF, 2.7 ml, 2.7 mmol), and HOAc(280 ul, 294 mg, 4.9 mmol) in THF (10 ml) was stirred at roomtemperature for 16 hours. An additional 900 μl of TBAF solution wasadded to the mixture and stirring was continued for two more hours. Thesolution was poured into saturated NaHCO₃ and extracted with EtOAc. TheEtOAc layer was washed with brine, dried (Na₂ SO₄), filtered andstripped to afford a yellow oil. The residue was chromatographed (flash,Merck SiO₂, 40% acetone in hexane) to afford the title compound (273 mg,58%) as a colorless oil.

TLC: R_(f) 0.37 (1:1--acetone:hexane)

I.(S)-4-[[[2-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A solution of compound H (254 mg, 0.485 mmol) in dioxane (3 ml) wastreated with 1N LiOH (1.8 ml, 1.8 mmol) at room temperature and themixture was subsequently heated at 55° C. under argon for 1.5 hours. Thesolvent was evaporated and the residue was chromatographed on HP-20eluting in succession with H₂ O (150 ml), 25% MeOH in H₂ O (100 ml), and50% MeOH in H₂ O (200 ml). The desired fractions were pooled andevaporated and the residue was taken up in H₂ O and lyophilized to giveExample 54 (210 mg, 82%) as a white solid.

TLC: R_(f) 0.50 (7:2:1--i-propanol:NH₄ OH:H₂ O) Anal. Calc'd for C₂₇ H₂₅FLi₂ NO₅ P * 1.01 H₂ O: C 61.69 H 5.18 N 2.67 F 3.61 P 5.89 Found: C61.74 H 5.16 N 2.62 F 3.55 P 5.82

Example 55(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-5H-indeno[1,2-b]pyridin-3-yl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A.β-(4-Fluorophenyl)-2,3-dihydro-α-(2-methyl-1-oxopropyl)-1-oxo-1H-indene-2-propanoicacid, ethyl ester

A -78° C. solution of LiN(TMS)₂ (1.0M in THF, 19 ml, 19 mmol) in dry THF(25 ml) was treated with a solution of 1-indanone (2.50 gm, 19 mmol) inTHF (3 ml) over a 2-minute period. After 50 minutes, a solution of thecompound prepared in part A of Example 53 (5.00 gm, 19 mmol) in THF (5ml) was added dropwise to the above solution. After one hour, themixture was quenched with saturated NH₄ Cl and warmed to roomtemperature. The mixture was diluted with H₂ O and subsequentlyextracted twice with Et₂ O. The combined Et₂ O extracts were washed withbrine, dried (Na₂ SO₄), filtered, and stripped to yield a brown cloudyoil. Flash chromatography (Merck SiO₂, 20% EtOAc in hexane) afforded theimpure title compound (4.671 gm, oil/solid) as a complex material ofdiastereomers. The material was used directly in the next reaction.

TLC: R_(f) 0.30, 0.24, & 0.20 (20% EtOAc in hexane)

B.4-(4-Fluorophenyl)-2-(1-methylethyl)-5H-indeno[1,2-b]pyridine-3-carboxylicacid, ethyl ester

A mixture of the crude compound of part A (4.671 gm), NH₄ OAc (2.74 gm,35.5 mmol), and Cu(OAc)₂ (5.88 gm, 29.5 mmol) in glacial HOAc (30 ml)was gently refluxed for 6 hours. The solution was cooled to roomtemperature and subsequently poured into an ice cold mixture ofconcentrated NH₄ OH (50 ml) in H₂ O (100 ml). The mixture was extractedonce with Et₂ O and once with EtOAc and the pooled organic extracts werewashed with H₂ O and brine, then dried (Na₂ SO₄), filtered and strippedto yield a dark brown oil. TLC showed the reaction had not gone tocompletion. The oil was flashed (Merck SiO₂, 10% EtOAc in hexane) togive the title compound as a pinkish oil (1.416 gm, 20% from compound1).

TLC: R_(f) 0.48 (20% EtOAc in hexane)

C.4-(4-Fluorophenyl)-2-(1-methylethyl)-5H-indeno[1,2-b]pyridine-3-methanol

A solution of the ester from part B (1.410 gm, 3.76 mmol) in dry THF (50ml) was treated with LiAlH₄ (740 mg, 19.5 mmol). The deep purplereaction mixture was stirred at room temperature for 7.5 hours. Thesolution was then cooled to 0° C. and quenched in succession with H₂ O(1 ml), 10% NaOH (1 ml), and H₂ O (3 ml). The solution was filtered andthe salts were washed with EtOAc and Et₂ O. The filtrate was dried (Na₂SO₄), filtered and stripped of solvent to afford an oil. The oil wasflashed (Merck SiO₂, 20% EtOAc in hexane) to provide the desired alcoholtitle compound (791 mg, 63%, 93% based on recovered ester) as a whitesolid and unreacted ester (454 mg). Analytically pure material wasobtained by recrystallization from hot EtOAc/hexane.

m.p. 165.5°-167° C. TLC: R_(f) 0.25 (20% EtOAc in hexane) Microanalysisfor C₂₂ H₂₀ FNO * 0.12 H₂ O: Calc'd: C 78.74 H 6.08 N 4.17 F 5.66 Found:C 78.74 H 6.15 N 4.17 F 5.64

D.4-(4-Fluorophenyl)-2-(1-methylethyl)-5H-indeno[1,2-b]pyridine-3-carboxaldehyde

A -78° C. solution of oxalyl chloride (280 ul, 407 mg, 3.21 mmol) in CH₂Cl₂ (10 ml) was treated dropwise with a solution of dry DMSO (455 ul,501 mg, 6.4 mmol) in CH₂ Cl₂ (1.5 ml). After 15 minutes, a solution ofthe alcohol from part C (764 mg, 2.29 mmol) in THF (3 ml) was addeddropwise to the above mixture. Twenty minutes after the addition, TEA (2ml) was added and the mixture was stirred at -78° C. for 5 minutes andthen warmed to room temperature. The mixture was diluted with Et₂ O andwashed twice with H₂ O and once with brine. The organic layer was dried(Na₂ SO₄), filtered, and stripped to give a solid residue. The residuewas flashed (Merck SiO₂, 10% EtOAc in hexane) providing the slightlyimpure aldehyde title compound (705 mg). The solid was recrystallizedfrom hot hexane to give the title compound (637 mg, 84%) as whitecrystals.

m.p. 142.5°-143.7° C. TLC: R_(f) 0.48 (20% EtOAc in hexane)

E.3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-5H-indeno[1,2-b]pyridine

A solution of carbon tetrabromide (940 mg, 2.83 mmol) in CH₂ Cl₂ (2 ml)was added over a 4-minute period to a cold (-7° C.) solution of thealdehyde from part D (626 mg, 1.89 mmol) and triphenylphosphine (1.486gm, 5.67 mmol) in CH₂ Cl₂ (11 ml). After the addition was complete, thecooling bath was removed and the mixture was stirred at room temperaturefor 30 minutes. The solution was quenched with saturated NaHCO₃ andextracted twice with CH₂ Cl₂. The combined organic layers were dried(Na₂ SO₄), filtered and concentrated. The concentrate waschromatographed (flash, Merck SiO₂, 20% CH₂ Cl₂ in hexane) to give theimpure dibromide title compound. The product was rechromatographed toprovide the title pure compound (632 mg, 69%) as a white foam.

TLC: R_(f) 0.32 (10% EtOAc in hexane)

F.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-5H-indeno[1,2-b]pyridin-3-yl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

A solution of the dibromide from part E (622 mg, 1.28 mmol) in THF (8ml) at -78° C. was treated with n-BuLi (2.5M in hexane, 1.2 ml, 3 mmol)over a 1-minute period and the resulting deep purple-blue solution wasstirred at -78° C. for 1 hour. The acetylenic anion solution was addeddropwise via cannula over a 2-minute period to a -78° C. solution of thephosphonochloridate from Example 57, part G in THF (8 ml). The resultingmixture was stirred at -78° C. for 30 minutes, then quenched with 50%saturated NH₄ Cl. The solution was warmed to 0° C. and poured intosaturated NaHCO₃. The aqueous phase was extracted once with Et₂ O. TheEt₂ O layer was washed with brine, dried (Na₂ SO₄), filtered andstripped to give an oil. The residue was chromatographed (flash, MerckSiO₂, 40% EtOAc in hexane) to afford the title compound as a colorlessfoam (305 mg, 31%).

TLC: R_(f) 0.25 (40% EtOAc in hexane)

G.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-5H-indeno[1,2-b]pyridin-3-yl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester

A mixture of the compound of part F (304 mg, 0.40 mmol),tetra-n-butylammonium fluoride (1.0M in THF, 1.6 ml, 1.6 mmol), and HOAc(115 ul, 121 mg, 2 mmol) in THF (8 ml) was stirred at room temperaturefor 20 hours. The solution was diluted with EtOAc and washed three timeswith 5% KHSO₄. The aqueous layers were back-extracted once with EtOAcand the pooled EtOAc layers were dried (Na₂ SO₄), filtered and strippedto afford a yellow oil. The oil was dissolved in Et₂ O, cooled to 0° C.and treated with excess diazomethane for 10 minutes. The excessdiazomethane was destroyed by the addition of HOAc and the solvent wasremoved in vacuo. The residue was chromatographed (flash, Merck SiO₂,40% acetone in hexane) to afford the title compound (165 mg, 79%) as ayellow foam.

TLC: R_(f) 0.31 (1:1--acetone:hexane)

H.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-5H-indeno[1,2-b]pyridin-3-yl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A solution of the compound of part G (164 mg, 0.314 mmol) in dioxane (3ml) was treated with 1N LiOH (1.1 ml, 1.1 mmol) at room temperature andthe mixture was subsequently heated at 65° C. under argon for 2 hours.The solvent was evaporated and the residue was chromatographed on HP-20,eluting in succession with H₂ O (200 ml), 25% MeOH in H₂ O (100 ml), and50% MeOH in H₂ O (200 ml). The desired fractions were pooled andevaporated and the residue was taken up in H₂ O and lyophilized to giveExample 55 (124 mg, 75%) as a pale yellow solid.

TLC: R_(f) 0.40 (7:2:1--i-propanol:NH₄ OH:H₂ O) Anal. Calc'd for C₂₇ H₂₃FLi₂ NO₅ P * 1.31 H₂ O: C 61.30 H 4.88 N 2.65 F 3.59 P 5.85 Found: C61.29 H 4.74 N 2.66 F 3.57 P 5.72

Example 56(S)-4-[[[5,6-Diphenyl-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A.β-(4-Fluorophenyl)-α-(2-methyl-1-oxopropyl)-Δ-oxo-γ-phenylbenzenepentanoicacid, ethyl ester

A -78° C. solution of LiN(TMS)₂ (1.0M in THF, 29 ml, 29 mmol) wastreated with a solution of deoxybenzoin (5.684 gm, 29 mmol) in THF (10ml) over a 2-minute period. After 20 minutes, a solution of the compoundof part A in Example 53 (5.468 gm, 20.7 mmol) in THF (5 ml) was addeddropwise to the above solution. The mixture was stirred at -78° C. forone hour and then warmed to 0° C. (the solution became clear orange).After 1.5 hours, the mixture was quenched with HOAc (3.3 ml), dilutedwith saturated NH₄ Cl and H₂ O and subsequently extracted with Et₂ O.The Et₂ O extract was washed with H₂ O and brine, then dried (Na₂ SO₄),filtered, and stripped to yield a solid/liquid mixture. The material wasused directly in the next reaction.

TLC: R_(f) 0.34, 0.28, & 0.24 (20% EtOAc in hexane)

B.4-(4-Fluorophenyl)-2-(1-methylethyl)-5,6-diphenyl-3-pyridinecarboxylicacid, ethyl ester

The aforementioned crude mixture of the compound from part A, NH₄ OAc(4.40 gm, 57.1 mmol), and Cu(OAc)₂ (12.5 gm, 62.6 mmol) in glacial HOAc(50 ml) was gently refluxed for 20 hours. The solution was cooled toroom temperature and subsequently poured into an ice cold mixture ofconcentrated NH₄ OH (60 ml) in H₂ O (70 ml). The mixture was extractedonce with Et₂ O and the organic extract was washed with H₂ O and brine,then dried (Na₂ SO₄), filtered and stripped to yield an oil whichsolidified on standing. The solid was dissolved in EtOAc and was flashed(Merck SiO₂, 10% EtOAc in hexane) to give a mixture of the titlecompound and deoxybenzoin as a solid. The solid was recrystallized fromhot EtOAc/hexane to provide pure ester 3 (5.473 gm, 60% from 1). Themother liquor contained solids (1.4 gm) which were comprised of a 1:1mixture of the title compound and deoxybenzoin.

m.p. 135.2°-136.3° C. TLC: R_(f) 0.51 (20% EtOAc in hexane)Microanalysis for C₂₉ H₂₆ FNO₂ : Calc'd: C 79.25 H 5.96 N 3.19 F 4.32Found: C 79.24 H 5.86 N 3.21 F 4.26

C. 4-(4-Fluorophenyl)-2-(1-methylethyl)-5,6-diphenyl-3-pyridinemethanol

A cold (0° C.) solution of the ester from part B (5.490 gm, 12.5 mmol)in dry THF (120 ml) was treated with LiAlH₄ (1.916 gm, 50.5 mmol). Theice bath was removed and the mixture was stirred at room temperature for1.75 hours. The solution was then cooled to 0° C. and quenched insuccession with H₂ O (2 ml), 10% NaOH (3 ml), and H₂ O (6 ml). Thesolution was filtered and the salts were washed with EtOAc. The filtratewas stripped of solvent to afford a yellow solid. The residue wasrecrystallized from hot EtOAc/hexane to provide the title compound(4.260 gm, 86%) as a white solid.

m.p. 169°-171° C. TLC: R_(f) 0.17 (20% EtOAc in hexane) Microanalysisfor C₂₇ H₂₄ FNO: Calc'd: C 81.58 H 6.09 N 3.52 F 4.78 Found: C 81.78 H6.17 N 3.61 F 4.66

D.4-(4-Fluorophenyl)-2-(1-methylethyl)-5,6-diphenyl-3-pyridinecarboxaldehyde

A -78° C. solution of oxalyl chloride (790 μl, 1.15 gm, 9.1 mmol) in CH₂Cl₂ (30 ml) was treated dropwise with a solution of dry DMSO (1.30 ml,1.43 gm, 18.3 mmol) in CH₂ Cl₂ (2.5 ml). After 15 minutes, a solution ofthe alcohol from part C (3.000 gm, 7.55 mmol) in THF (9 ml) was addeddropwise to the above mixture. Twenty five minutes after the addition,TEA (6 ml) was added and the mixture was stirred at -78° C. for 5minutes and then warmed to room temperature. The mixture was dilutedwith Et₂ O and washed twice with H₂ O and once with brine. The organiclayer was dried (Na₂ SO₄), filtered, and stripped to give a solidresidue. The solid was recrystallized from hot Et₂ O/hexane to give thealdehyde title compound (2.621 gm, 88%) as white needles.

m.p. 136°-137.5° C. TLC: R_(f) 0.50 (20% EtOAc in hexane)

E.3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-5,6-diphenylpyridine

A solution of carbon tetrabromide (3.354 gm, 10.1 mmol) in CH₂ Cl₂ (10ml) was added over a 5-minute period to a cold (-6° C.) solution of thealdehyde from part D (2.649 gm, 6.70 mmol) and triphenylphosphine (5.270gm, 20.1 mmol) in CH₂ Cl₂ (30 ml). After the addition was complete, thecooling bath was removed and the mixture was stirred at room temperaturefor 40 minutes. The solution was quenched with saturated NaHCO₃ andextracted once with CH₂ Cl₂. The organic layer was dried (Na₂ SO₄),filtered and concentrated. The concentrate was chromatographed (flash,Merck SiO₂, 50% CH₂ Cl₂ in hexane) to give dibromide title compound as afoam which solidified on standing. Recrystallization of the materialprovided the pure title compound (3.305 gm, 89%) as a white solid.

m.p. 154.5°-157.5° C. TLC: R_(f) 0.56 (20% EtOAc in hexane)

F.(S)-4-[[[5,6-Diphenyl-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methylester

A solution of the dibromide from part E (2.500 gm, 4.53 mmol) in THF (12ml) at -78° C. was treated with n-BuLi (2.5M in hexane, 3.90 ml, 9.7mmol) over a 1-minute period and the resulting clear brown solution wasstirred at -78° C. for 1 hour. The acetylenic anion solution was addeddropwise via cannula over a 3-minute period to a -78° C. solution of thephosphonochloridate from Example 57, part G in THF (15 ml). Theresulting mixture was stirred at -78° C. for 30 minutes, then quenchedwith 50% saturated NH₄ Cl. The solution was warmed to 0° C. and pouredinto saturated NaHCO₃. The aqueous phase was extracted once with Et₂ O.The Et₂ O layer was washed with brine, dried (Na₂ SO₄), filtered andstripped to give an orange oil. The residue was chromatographed (flash,Merck SiO₂, 40% EtOAc in hexane) to afford the title compound as acolorless foam (2.670 gm, 71%).

TLC: R_(f) 0.25 (40% EtOAc in hexane)

G.(S)-4-[[[5,6-Diphenyl-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methylester

A mixture of the compound of part F (2.617 gm, 3.17 mmol),tetra-n-butylammonium fluoride (1.0M in THF, 9.5 ml, 9.5 mmol), and HOAc(725 ul, 760 mg, 12.7 mmol) in THF (20 ml) was stirred at roomtemperature for 17 hours. The solution was diluted with EtOAc and washedtwice with 5% KHSO₄. The aqueous layers were back-extracted once withEtOAc and the pooled EtOAc layers were dried (Na₂ SO₄), filtered andstripped to afford a yellow oil. The oil was dissolved in Et₂ O, cooledto 0° C. and treated with excess diazomethane for 10 minutes. The excessdiazomethane was destroyed by the addition of HOAc and the solvent wasremoved in vacuo. The residue was chromatographed (flash, Merck SiO₂,40% acetone in hexane followed by 1:1 acetone:hexane) to afford thetitle compound (1.408 gm, 76%) as a white solid.

m.p. 143°-145.5° C. TLC: R_(f) 0.36 (1:1--acetone:hexane)

H.(S)-4-[[[5,6-Diphenyl-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A solution of the compound from part G (498 mg, 0.85 mmol) in dioxane (6ml) was treated with 1N NaOH (3.0 ml, 3.0 mmol) at room temperature andthe mixture was subsequently heated at 60° C. under argon for 1.5 hours.The solvent was evaporated and the residue was chromatographed on HP-20eluting in succession with H₂ O (200 ml), 25% MeOH in H₂ O (100 ml), and50% MeOH in H₂ O (200 ml). The desired fractions were pooled andevaporated and the residue was taken up in H₂ O and lyophilized to giveExample 56 (480 mg, 91%) as a white solid.

TLC: R_(f) 0.18 (8:1:1--CH₂ Cl₂ :HOAc:MeOH) Anal. Calc'd for C₃₂ H₂₇FNNa₂ O₅ P * 1.22 H₂ O: C 61.64 H 4.76 N 2.25 F 3.05 P 4.97 Found: C61.66 H 4.95 N 2.30 F 3.14 P 4.88

Example 57(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-methylphenyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A. 3-(4-Fluorophenyl)-1-(2-methylphenyl)-2-propen-1-one

A mixture of 4-fluorobenzaldehyde (12.13 ml, 110 mmol, from Aldrich) and2'-methylacetophenone (14.4 ml, 110 mmol, Aldrich) in absolute ethanol(120 ml) was treated with a solution of sodium ethoxide in ethanol (21%by weight solution; 4.1 ml, 11 mmol). The clear, dark reaction mixturewas stirred at room temperature under argon for 24 hours. The reactionmixture was concentrated to 1/3 volume, and partitioned between 50%saturated NH₄ Cl and EtOAc. The layers were separated and the organiclayer washed twice with H₂ O and brine, then dried (Na₂ SO₄) andconcentrated under reduced pressure. The product was obtained as ayellow oil (26.0 g, 100.0%) and used without further purification.

R_(f) 0.54 (30% EtOAc/hexane), UV

B.β-(4-Fluorophenyl)-2-methyl-α-(2-methyl-1-oxopropyl)-Δ-oxobenzenepentanoicacid, ethyl ester

A mixture of the part A compound (15.18 g, 63.2 mmol) and ethylisobutyrylacetate (10,0 g, 63.2 mmol) in absolute ethanol (150 ml) wastreated with a solution of sodium ethoxide in ethanol (21% by weightsolution, 2.43 ml, 6.32 mmol). A precipitate soon fell out of solution.After stirring at room temperature for 16 hours, the mixture was cooledto -10° C. and the precipitate was collected by filtration (15.17 g,white solids). The filtrate was concentrated to 1/3 volume, partitionedbetween 50% saturated NH₄ Cl and EtOAC. The layers were separated andthe organic layer was washed with H₂ O (twice) and brine, then dried(Na₂ SO₄) and concentrated under reduced pressure. The obtained oil wasdissolved in hot hexane and cooled to produce a solid (6.0 g). Bothcrops were combined and recrystallized from hot hexane, yielding thetitle compound as a white solid (21.07 g, 84.0%; mixture ofdiastereomers).

m.p. 105°-106° C. R_(f) 0.42 (30% EtOAc/hexane), UV Analysis for C₂₄ H₂₇FO₄ : Calc'd: C, 72.34; H, 6.83; F, 4.77 Found: C, 72,12; H, 6.89; F,4.72

C.4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-methylphenyl)-3-pyridinecarboxylicacid, ethyl ester

A mixture of the part B compound (21.0 g, 52.70 mmol), ammonium acetate(12.18 g, 158.3 mmol) and copper (II) acetate (25.9 g, 131.75 mmol) inglacial acetic acid (150 ml) was heated at 110° C. for 20 hours (TLCindicated only a trace of starting material). The solution was cooled toroom temperature and poured into an ice cold mixture of concentrated NH₄OH (180 ml) and H₂ O (240 ml). The mixture was extracted with ether andthe ether extract was washed with H₂ O (twice) and brine, then dried(MgSO₄), filtered and concentrated to yield the title compound as ayellow oil (19.9 g, 100.0%). The crude material was used directly in thenext reaction.

R_(f) 0.58 (30% EtOAc/hexane), UV

D.4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-methylphenyl)-3-pyridinemethanol

A cold (0° C.) solution of the crude ester from part C (19.9 g, 52.7mmol) in dry THF (250 ml) was treated with LiAlH₄ (6.00 g, 158 mmol).Ten minutes after the addition, the cooling bath was removed and thereaction mixture was stirred at room temperature for 2 hours (TLCindicated the absence of starting material). The dark solution wascooled to 0° C. and, while stirring, carefully quenched first bydropwise addition of 6.0 ml of H₂ O in THF (50 ml), then with 6.0 ml 15%NaOH, and finally with 12.0 ml H₂ O. The precipitated aluminum saltswere filtered and washed with EtOAc and ether. The filtrate was washedwith H₂ O and brine, dried (Na₂ SO₄) filtered and concentrated underreduced pressure. The solid residue was recrystallized from hotEtOAc/hexane, yielding the compound as a white solid (13.5 g, 76.7%,from the part C compound).

m.p. 114°-115° C. R_(f) 0.51 (30% EtOAc/hexane), UV Analysis for C₂₂ H₂₂NFO×0.22 H₂ O: Calc'd: C, 77.84; H, 6.67; N,4.13; F, 5.60 Found: C,78.20; H, 6.80; N,3.77; F, 5.64

E.4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-methylphenyl)-3-pyridinecarboxaldehyde

A -78° C. solution of oxalyl chloride (1.25 ml, 14.3 mmol) in CH₂ Cl₂(80 ml) was treated dropwise with a solution of dry DMSO (2.03 ml, 28.6mmol) in CH₂ Cl₂ (2 ml). After 15 minutes, a solution of the alcoholfrom part D (4.0 g, 11.93 mmol) in CH₂ Cl₂ (15 ml) was added dropwise tothe above solution. After 20 minutes, triethylamine (9.9 ml, 71.58 mmol)was added and the mixture was stirred at -78° C. for 20 minutes and thenwarmed to room temperature. The mixture was diluted with ether andwashed with H₂ O (twice) and brine, then dried (MgSO₄), filtered andconcentrated under reduced pressure. The yellow solid residue (4.0 g)was recrystallized from hot hexane. The title compound was obtained as awhite crystalline material (3.0 g, 75.6%).

m.p. 138°-140° C. R_(f) 0.57 (30% EtOAc/hexane), UV Analysis for C₂₂ H₂₀NFO: Calc'd: C, 79.25; H, 6.05; N,4.20; F, 5.70 Found: C, 79.13; H,6.08; N,4.19; F, 5.53

F.3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-6-(2-methylphenyl)pyridine

A solution of carbon tetrabromide (4.47 g, 13.5 mmol) in CH₂ Cl₂ (15 ml)was added dropwise over a 5-minute period to a cold (0° C.) solution ofthe aldehyde from part E (3.0 g, 9.0 mmol) and triphenylphosphine (7.08g, 127.0 mmol) in CH₂ Cl₂ (60 ml). The mixture was stirred at 0° C. for10 minutes and then at room temperature for 10 minutes. The solution wasquenched with saturated NaHCO₃ and extracted twice with CH₂ Cl₂. Thecombined organic layers were dried (Na₂ SO₄), filtered, concentrated tohalf volume and applied on Merck silica gel column (50% CH₂ Cl₂/hexane). Flash chromatography afforded the title compound as acolorless viscous oil that slowly solidified on standing (4.0 g, 90.0%).

m.p. 108°-110° C. R_(f) 0.62 (20% EtOAc/hexane), UV Analysis for C₂₃ H₂₀NFBr₂ : Calc'd: C, 56.47; H, 4.12; N, 2.86; F, 3.88 Found: C, 56,38; H,4.04; N, 2.90; F, 3.71

G.(S)-4-Chloromethoxyphosphonyl-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

The title compound was prepared as described in Example 4, part C, firstparagraph, except as described below.(S)-4-(Hydroxymethoxyphosphinyl)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester, dicyclohexylamine (1:1) salt (3.88 g, 6.15 mmol waspartitioned between EtOAc and 5% KHSO₄. The EtOAc layer was washed (3×5% KHSO₄, then with brine), dried (Na₂ SO₄), filtered and concentratedunder reduced pressure to afford the phosphinic acid monomethyl ester asa colorless oil. The oil was dissolved in dry CH₂ Cl₂ (15 ml) andtreated with N,N-diethyltrimethylsilylamine (2.33 ml, 12.3 mmol). Afterstirring at room temperature for 1 hour, the solvent was removed invacuo and the residue was azeotroped with dry benzene (30 ml). Theresidue was redissolved in dry CH₂ Cl₂ (15 ml), cooled to 0° C. andtreated with 2 drops of DMF and oxalyl chloride (610 ul, 7.0 mmol).After 15 minutes, the solution was warmed to room temperature andstirred for an additional 60 minutes. The solvent was removed underreduced pressure and the yellow residue (the phosphonochloridatecompound G) was azeotroped with dry benzene and dried in vacuo for 1hour.

H.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-methylphenyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

A solution of the dibromide from part F (2.0 g, 4.1 mmol) in THF (10 ml)at -78° C. was treated with n-BuLi (2.5M in hexane, 3.3 ml, 8.2 mmol)over a 1-minute period. The dark-green reaction mixture was stirred for1 hour at -78° C. and then transferred via cannula to a -78° C. solutionof the phosphonochloridate from part G in THF (10 ml). The green-brownreaction mixture was stirred at -78° C. for 30 minutes and quenched with50% saturated NH₄ Cl. After warming to room temperature, the solutionwas diluted with H₂ O and poured into saturated NaHCO₃. The layers wereseparated and the aqueous portion was back-extracted once with ether.The combined organic layers were washed with brine, dried (Na₂ SO₄),filtered and concentrated under reduced pressure. The orange oilyresidue was purified by flash chromatography (Merck silica gel, 30%EtOAc/hexane) to afford the title compound as a pale yellow foam (1.9 g,60.7%).

R_(f) 0.31 (40% EtOAc/hexane), UV

I.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-methylphenyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

To a solution of the acetylinic phosphonate from part H (1.85 g, 2.42mmol) in THF (15 ml) was added HOAc (0.55 ml, 9.68 mmol) followed bytetra-n-butylammonium fluoride (1.0M in THF, 7.26 mmol, 7.26 ml). Thereaction mixture was stirred at room temperature under argon for 20hours. The solution was diluted with EtOAc and washed three times with5% KHSO₄. The aqueous layer was back-extracted with EtOAc (twice) andthe combined organic extracts were dried (Na₂ SO₄), filtered andconcentrated under reduced pressure. The yellow-orange oil was dissolvedin ether, cooled to 0° C. and treated with excess diazomethane for 30minutes. The excess diazomethane was destroyed by the addition of HOAc.Solvent removal gave an oily orange residue, which was purified by flashchromatography (Merck silica gel, 40% EtOAc/hexane). The title compoundwas obtained as a pale yellow oil (0.51 g, 41.0%).

R_(f) 0.44 (50% acetone/hexane), UV

J.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-methylphenyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

The diester from part I (0.50 g, 0.95 mmol) in dioxane (5 ml) wastreated with 1N LiOH (3.3 ml, 3.3 mmol) at room temperature and thenheated at 50° C. for 2.5 hours and at 60° C. for 1 hour (TLC indicatedthe absence of starting material). The solvent was evaporated and theresidue was dissolved in H₂ O and chromatographed on HP-20 resin elutingfirst with H₂ O (200 ml), followed by 25% MeOH/H₂ O (100 ml), 50%MeOH/H₂ O (250 ml) and finally MeOH (100ml). The collected productfractions were evaporated, dissolved in H₂ O, filtered, frozen andlyophilized to afford Example 57 as a white lyophilate (0.25 g, 60.7%).

R_(f) 0.50 (8:1:1--CHCl₂ :CH₃ OH:HOAc), UV Analysis for C₂₄ H₂₇ FLi₂ NO₅P×1.1 H₂ O: Calc'd: C 61.28 H 5.56 N 2.65 F 3.59 P 5.82 Found: C 61.23 H5.28 N 2.94 F 3.44 P 6.02

Example 58 (S)-4-[[[6-(1,3-Benzodioxol-4-yl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

A. 1,3-Benzodioxole-4-carboxaldehyde

A mixture of 2,3-dihydroxybenzaldehyde (25.0 g, 180 mmol; from AldrichChemical Co.) and potassium fluoride (49.3 g, 830 mmol) in DMF (500 ml)was heated at 50° C. for 20 minutes. The reaction mixture was cooled toroom temperature and dibromomethane (44.5 g, 250 mmol) was added and thedark reaction mixture was heated at 120° C. for 3 hours. Afterfiltration of the cooled mixture, the filtrate was poured into 1 literH₂ O and extracted with ether (2×200 ml). The combined ether extractswere washed with H₂ O (2×200 ml), 0.5N NaOH (2×200 ml) and brine, thendried (MgSO₄) and concentrated, yielding the title compound I as ayellow oil (19.8 g, 73.0%).

R_(f) 0.56 (40% EtOAc/hexane), UV

B. α-Methyl-1,3-benzodioxole-4-methanol

A -78° C. solution of the compound of part A (19.0 g, 126.6 mmol) inether (400 ml) was treated with methylmagnesium bromide (3M in ether,55.0 ml, 165 mmol; from Aldrich Chemical Co.) over a 30-minute periodusing a syringe pump. After stirring for 1 hour the reaction mixture(heavy suspension) was carefully poured into saturated NH₄ Cl (250 ml).The layers were separated and the aqueous layer was extracted with ether(three times). The combined ether extracts were washed with H₂ O andbrine, then dried (MgSO₄) and concentrated. The oily residue waspurified by flash chromatography (Merck Silica gel, 10% EtOAc/hexane).The title compound was obtained as a colorless oil which slowlysolidified on standing (13.3 g, 63.6%).

m.p. 45°-46° C. R_(f) 0.39 (40% EtOAc/hexane), UV Anal. Calc'd for C₉H₁₀ O₃ : Calc'd: C, 65.05; H, 6.07; Found: C, 64.71; H, 6.00

C. 1-(1,3-Benzodioxol-4-yl-1-ethanone

A -78° C. solution of oxalyl chloride (8.68 ml, 99.6 mmol) in CH₂ Cl₂(120 ml) was treated dropwise with a solution of dry DMSO (14.2 ml,199.2 mmol) in CH₂ Cl₂ (20 ml). After 15 minutes, a solution of thealcohol from part B (13.5 g, 83.0 mmol) in CH₂ Cl₂ (25 ml) was addeddropwise to the above solution. After 20 minutes, triethylamine (34.7ml) was added and the mixture was stirred at -78° C. for 20 minutes andthen warmed to room temperature. The mixture was diluted with ether andwashed twice with H₂ O and brine, then dried (MgSO₄), filtered andconcentrated under reduced pressure. The solid residue wasrecrystallized from hot hexane. The title compound was obtained as whitecrystals (13.5 g, 82.8%).

m.p. 94°-95° C. R_(f) 0.49 (30% EtOAc/hexane), UV Anal. Calc'd for C₉ H₈O: Calc'd: C, 65.87; H, 4.91; Found: C, 65.54; H, 4.75

D. 1-(1,3-Benzodioxol-4-yl)-3-(4-fluorophenyl)-2-propen-1-one

A mixture of 4-fluorobenzaldehyde (8.78 ml, 81.8 mmol, from AldrichChemical Co.) and the compound of part C (13.4 g, 81.8 mmol) in absoluteethanol (110 ml) was treated with a solution of sodium ethoxide inethanol (21% by weight solution; 3.10 ml, 8.18 mmol). A precipitate soonfell out of solution. After stirring at room temperature for 18 hours,the mixture was cooled to -10° C. and the precipitate was collected byfiltration. The solid was washed with cold ethanol and dried in vacuoand recrystallized from hot hexane. The title compound was obtained as alight yellow solid (12.5 g, 56.6%).

m.p. 248°-250° C. R_(f) 0.68 (30% EtOAc/hexane), UV Anal. Calc'd for C₁₆H₁₁ FO₃ ×0.18 H₂ O: Calc'd: C, 70.27; H, 4.19; F, 6.95; Found: C, 70.27;H, 3.87; F, 6.65

E.β-(4-Fluorophenyl)-α-(2-methyl-1-oxopropyl)-Δ-oxo-1,3-benzodioxol-4-ylpentanoic acid, ethyl ester

A slurry of the compound of part D (12.5 g, 46.25 mmol) and ethylisobutyrylacetate (7.46 ml, 46.25 mmol) in absolute ethanol (120 ml) wastreated with a solution of sodium ethoxide in absolute EtOH (21% byweight solution, 1.70 ml, 4.62 mmol). A white precipitate soon fell outof solution. After stirring at room temperature overnight, the mixturewas cooled to -10° C. and the precipitate was collected by filtration.The solid was washed with cold ethanol, dried in vacuo andrecrystallized from hot hexane. The title compound was obtained as awhite solid (14.6 g, 75.0%).

m.p. 109°-110° C. R_(f) 0.56 (30% EtOAc/hexane), UV Anal. Calc'd for C₂₄H₂₅ FO₆ ×0.19 H₂ O: Calc'd: C, 66.75; H, 5.92; F, 4.40; Found: C, 66.75;H, 5.65; F, 4.36

F.6-(1,3-Benzodioxol-4-yl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinecarboxylicacid, ethyl ester

A mixture of the compound of part E (13.5 g, 31.5 mmol), ammoniumacetate (7.28 g, 94.5 mmol) and copper (II) acetate (15.70 g, 78.75mmol) in glacial acetic acid (90 ml) was heated at 110° C. for 18 hours(TLC indicated the absence of starting material). The solution wascooled to room temperature and poured into an ice cold mixture ofconcentrated NH₄ OH (110 ml) and H₂ O (150 ml). The mixture wasextracted with ether and the ether extract was washed twice with H₂ Oand brine, then dried (MgSO₄), filtered and concentrated to yield ayellow solid residue. The crude material was recrystallized from hothexane, yielding the title compound as a pale yellow solid (7.52 g,58.3%).

m.p. 148°-150° C. R_(f) 0.62 (30% EtOAc/hexane), UV Anal. Calc'd for C₂₄H₂₂ NFO₄ : Calc'd: C, 70.75; H, 5.44; N, 3.44; F, 4.66; Found: C, 70.92;H, 5.53; N, 3.49; F, 4.62

G.6-(1,3-Benzodioxol-4-yl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinemethanol

A cold (0° C.) solution of the ester from part F (7.0 g, 17.05 mmol) indry THF (85 ml) was treated with LiAlH₄ (1.94 g, 51.15 mmol). Tenminutes after the addition, cooling bath was removed and the reactionmixture was stirred at room temperature for 3 hours (TLC indicated theabsence of starting material). The dark mixture was cooled to 0° C. and,while stirring, carefully quenched first by a dropwise addition of 1.94ml of H₂ O in THF (15 ml), then 1.94 ml 15% NaOH and finally 4.0 ml H₂O. The precipitated aluminum salts were filtered and washed with EtOAcand ether. The filtrate was washed with H₂ O and brine, dried (Na₂ SO₄)filtered and concentrated under reduced pressure. The solid residue wasrecrystallized from hot EtOAc/hexane, yielding the title compound as anoff-white solid (6.0 g, 96.7%).

m.p. 114°-115° C. R_(f) 0.44 (30% EtOAc/hexane), UV Anal. Calc'd for C₂₂H₂₀ NFO₃ : Calc'd: C, 72.31; H, 5.52; N, 3.83; F, 5.20; Found: C, 72.14;H, 5.40; N, 3.83; F, 5.07

H.6-(1,3-Benzodioxol-4-yl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinecarboxaldehyde

A -78° C. solution of oxalyl chloride (0.57 ml, 6.57 mmol) in CH₂ Cl₂(80 ml) was treated dropwise with a solution of dry DMSO (0.93 ml, 13.12mmol) in CH₂ Cl₂ (2 ml). After 15 minutes, a solution of the alcoholfrom part G (2.0 g, 5.47 mmol) in CH₂ Cl₂ (15 ml) was added dropwise tothe above solution. After 20 minutes, triethylamine (4.57 ml) was addedand the mixture was stirred at -78° C. for 20 minutes and then warmed toroom temperature. The mixture was diluted with ether and washed twicewith H₂ O and brine, dried (MgSO₄), filtered and concentrated underreduced pressure. The yellow solid residue was recrystallized from hothexane. The title compound (two crops) was obtained as a pale yellowsolid (1.65 g, 83.3%).

m.p. 121°-122° C. R_(f) 0.57 (30% EtOAc/hexane), UV Anal. Calc'd for C₂₂H₁₈ NFO₃ : Calc'd: C, 72.71; H, 4.99; N, 3.86; F, 5.23; Found: C, 72.40;H, 5.05; N, 3.73; F, 5.33

I.6-(1,3-Benzodioxol-4-yl)-3-(2,2-dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)pyridine

A solution of carbon tetrabromide (3.28 g, 6.6 mmol) in CH₂ Cl₂ (15 ml)was added dropwise over a 5-minute period to a cold (0° C.) solution ofthe aldehyde from part H (1.60 g, 4.4 mmol) and triphenylphosphine (3.46g, 13.2 mmol) in CH₂ Cl₂ (60 ml). The mixture was stirred at 0° C. for10 minutes and then at room temperature for 10 minutes. The solution wasquenched with saturated NaHCO₃ and extracted twice with CH₂ Cl₂. Thecombined organic layers were dried (Na₂ SO₄), filtered, concentrated tohalf volume and applied on Merck silica gel column (50% CH₂ Cl₂/hexane). Flash chromatography afforded the title compound as acolorless viscous oil which slowly solidified on standing (1.65 g,89.0%).

m.p. 129°-131° C. R_(f) 0.63 (30% EtOAc/hexane), UV Anal. Calc'd for C₂₃H₁₈ NO₂ FBr₂ Calc'd: C, 53.20; H, 3.49; N, 2.70; F, 3.66; Br, 30.78;Found: C, 53.14; H, 3.45; N, 2.66; F, 3.49; Br, 30,47

J.(S)-4-[[[6-(1,3-Benzodioxol-4-yl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methylester

A solution of the dibromide of part I (1.68 g, 3.17 mmol) in THF (10 ml)at -78° C. was treated with n-BuLi (2.5M in hexane, 2.53 ml, 6.34 mmol)over a 1-minute period. The dark-green reaction mixture was stirred for1 hour at -78° C. and then transferred via cannula to a -78° C. solutionof the phosphonochloridate prepared in Example 57, part G in THF (10ml). The green-brown reaction mixture was stirred at -78° C. for 30minutes and quenched with 50% saturated NH₄ Cl. After warming to roomtemperature, the solution was diluted with H₂ O and poured intosaturated NaHCO₃. The layers were separated and the aqueous layer wasextracted once with ether. The combined organic layers were washed withbrine, dried (Na₂ SO₄), filtered and concentrated under reducedpressure. The orange oily residue was purified by flash chromatography(Merck silica gel, 25% EtOAc/hexane) to afford the title compound as apale yellow foam (0.68 g, 27%).

R_(f) 0.31 (40% EtOAc/hexane), UV

K.(S)-4-[[[6-(1,3-Benzodioxol-4-yl)-4-(4-fluorophenyI)-2-(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methylester

To a solution of the acetylinic phosphonate of part J (0.94 g, 1.18mmol) in THF (15 m) was added HOAc (0.27 ml, 4.72 mmol), followed bytetra-n-butylammonium fluoride (1.0M in THF, 3.54 ml, 3.54 mmol). Thereaction mixture was stirred at room temperature under argon for 20hours. The solution was diluted with EtOAc and washed 3× 5% KHSO₄. Theaqueous layer was back-extracted twice with EtOAc and the combinedorganic extracts were dried (Na₂ SO₄), filtered and concentrated underreduced pressure. The yellow-orange oil was dissolved in ether (a fewdrops of THF were added to obtain a clear solution), cooled to 0° C. andtreated with excess diazomethane for 30 minutes. The excess diazomethanewas destroyed by the addition of HOAc. Solvent removal gave an orangeoily residue, which was purified by flash chromatography (Merck silicagel, 40% acetone/hexane). The title compound was obtained as a colorlessoil (0.24 g, 37.0%).

R_(f) 0.30 (50% acetone/hexane) UV

L.(S)-4-[[[6-(1,3-Benzodioxol-4-yl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, dilithium salt

The diester from part K (0.24 g, 0.43 mmol) in dioxane (5 ml) wastreated with 1N LiOH (1.51 ml, 1.51 mmol) at room temperature and thenheated at 50° C. for 2.5 hours (TLC indicated the absence of startingmaterial). The solvent was evaporated and the residue waschromatographed on HP-20 resin eluting first with H₂ O (200 ml),followed by 25% MeOH/H₂ O (200 ml), 50% MeOH/H₂ O (250 ml) and finallyMeOH (100 ml). The collected product fractions were evaporated,dissolved in H₂ O, filtered, frozen and lyophilized to give Example 58as a white lyophilate (0.22 g, 95.0%).

R_(f) 0.55 (8:1:1--CH₂ Cl₂ :CH₃ OH:HOAc), UV Anal. Calc'd for C₂₇ H₂₃FLi₂ NO₇ ×1.24 H₂ O Calc'd: C, 57.65; H, 4.62; N, 2.49; F, 3.38; P,5.51; Found: C, 57.34; H, 4.50; N, 2.89; F, 3.30; P, 5.41.

Example 59(S)-4-[[[5-Ethyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A.γ-Ethyl-β-(4-fluorophenyl)-α-(2-methyl-1-oxopropyl)-.DELTA.-oxobenzenepentanoicacid, ethyl ester

A -78° C. solution of LiN(TMS)₂ (1.0M in THF, 23 ml, 23 mmol) and THF(15 ml) was treated with a solution of butyrophenone (3.365 gm, 22.7mmol) in THF (2 ml) over a 1-minute period. After 60 minutes, a solutionof the compound prepared in Example 53, part A (5.000 gm, 18.9 mmol) inTHF (5 ml) was added dropwise to the above solution. The mixture wasstirred at -78° C. for 45 minutes and then warmed to 0° C. After 25minutes, the mixture was quenched with HOAc (1.3 ml), diluted withsaturated NH₄ Cl and H₂ O and subsequently extracted with Et₂ O. The.Et₂ O extract was washed with brine, then dried (Na₂ SO₄), filtered, andstripped to yield a yellow oil. The material was used directly in thenext reaction.

TLC: R_(f) 0.43, 0.33, & 0.30 (20% EtOAc in hexane)

B.5-Ethyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxylicacid, ethyl ester

The aforementioned crude mixture of the compound of part A, NH₄ OAc(4.455 gm, 58 mmol), and Cu(OAc)₂ (9.92 gm, 49.7 mmol) in glacial HOAc(50 ml) were gently refluxed for 25 hours. The solution was cooled toroom temperature and subsequently poured into an ice cold mixture ofconcentrated NH₄ OH (78 ml) in H₂ O (150 ml). The mixture was extractedonce with Et₂ O the organic extract was washed with H₂ O and brine, thendried (Na₂ SO₄), filtered and stripped to yield a brown oil. The residuewas flashed (Merck SiO₂, 10% EtOAc in hexane) to give the title compoundas an oil (5.350 gm) which was contaminated with butyrophenone.

TLC: R_(f) 0.48 (20% EtOAc in hexane)

C.5-Ethyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinemethanol

A cold (0° C.) solution of the impure ester from part B (5.335 gm) indry THF (150 ml) was treated with LiAlH₄ (1.645 gm, 43.3 mmol). The icebath was removed and the mixture was stirred at room temperature for 4hours. The solution was then cooled to 0° C. and quenched in successionwith H₂ O (1.5 ml), 10% NaOH (2 ml), and H₂ O (3.5 ml). The solution wasfiltered and the salts were washed with EtOAc and THF. The filtrate wasstripped of solvent to afford a solid. The residue was recrystallizedfrom hot EtOAc/hexane to provide the title compound (3.540 gm, 53% fromthe compound from Example 53, part A as a white solid.

m.p. 228.5°-230° C. TLC: R_(f) 0.16 (20% EtOAc in hexane) Microanalysisfor C₂₃ H₂₄ FNO: Calc'd: C 79.05 H 6.92 N 4.01 F 5.44 Found: C 78.98 H6.87 N 4.08 F 5.28

D.5-Ethyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde

A -78° C. solution of oxalyl chloride (600 μl, 873 mg, 6.9 mmol) in CH₂Cl₂ (30 ml) was treated dropwise with a solution of dry DMSO (1.00 ml,1.10 gm, 14.1 mmol) in CH₂ Cl₂ (1 ml). After 15 minutes, a solution ofthe alcohol from part C (2.000 gm, 5.7 mmol) in THF (15 ml) was addeddropwise to the above mixture. Fifteen minutes after the addition, TEA(4.5 ml) was added and the mixture was stirred at -78° C. for 3 minutesand then warmed to room temperature. The mixture was diluted with Et₂ Oand washed twice with H₂ O and once with brine. The organic layer wasdried (Na₂ SO₄), filtered, and stripped to give a solid residue. Theresidue was flashed (LPS-1, CH₂ Cl₂) to obtain a solid which wasrecrystallized from hot hexane to give the aldehyde title compound(1.715 gm, 86%) as an amorphous white solid.

m.p. 122°-123.8° C. TLC: R_(f) 0.51 (20% EtOAc in hexane) Microanalysisfor C₂₃ H₂₂ FNO: Calc'd: C 79.51 H 6.38 N 4.03 F 5.47 Found: C 79.35 H6.40 N 4.12 F 5.36

E.3-(2,2-Dibromoethenyl)-5-ethyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridine

A solution of carbon tetrabromide (2.35 gm, 7.1 mmol) in CH₂ Cl₂ (8 ml)was added over a 7-minute period to a cold (-5° C.) solution of thealdehyde from part D (1.630, 4.7 mmol) and triphenylphosphine (3.750 gm,14.3 mmol) in CH₂ Cl₂ (20 ml). After the addition was complete, thecooling bath was removed and the mixture was stirred at room temperaturefor 25 minutes. The solution was quenched with saturated NaHCO₃ andextracted twice with CH₂ Cl₂. The organic layers were dried (Na₂ SO₄),filtered and concentrated. The concentrate was chromatographed (flash,Merck SiO₂, 30% CH₂ Cl₂ in hexane followed by 30% hexane in CH₂ Cl₂) togive the dibromide title compound as a foam, which solidified onstanding. Recrystallization of the material from CH₂ Cl₂ /hexaneprovided the pure title compound (2.237 gm, 95%) as white needles.

m.p. 155.5°-157° C. TLC: R_(f) 0.40 (10% EtOAc in hexane) Microanalysisfor C₂₄ H₂₂ Br₂ FN: Calc'd: C 57.28 H 4.41 N 2.78 F 3.78 Br 31.76 Found:C 57.19 H 4.20 N 2.75 F 3.77 Br 31.99

F.(S)-4-[[[5-Ethyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methylester

A solution of the dibromide from part E (1.500 gm, 3.0 mmol) in THF (8ml) at -78° C. was treated with n-BuLi (2.5M in hexane, 2.5 ml, 6.3mmol) over a 1-minute period and the resulting clear brown solution wasstirred at -78° C. for 50 minutes. The acetylenic anion solution wasadded dropwise via cannula over a 5-minute period to a -78° C. solutionof the phosphonochloridate from Example 57, part G, in THF (12 ml). Theresulting mixture was stirred at -78° C. for 35 minutes, then quenchedwith 50% saturated NH₄ Cl. The solution was warmed to 0° C. and pouredinto saturated NaHCO₃. The aqueous phase was extracted once with Et₂ O.The Et₂ O layer was washed with brine, dried (Na₂ SO₄), filtered andstripped to give an orange oil. The residue was chromatographed (flash,Merck SiO₂, 40 % EtOAc in hexane) to afford the title compound as acolorless foam (1.726 gm, 74%).

TLC: R_(f) 0.28 (40% EtOAc in hexane)

G.(S)-4-[[[5-Ethyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methylester

A mixture of the part F compound (1.709 gm, 2.20 mmol),tetra-n-butylammonium fluoride (1.0M in THF, 6.6 ml, 6.6 mmol), and HOAc(500 μl, 525 mg, 8.7 mmol) in THF (10 ml) was stirred at roomtemperature for 18 hours. The solution was diluted with EtOAc and washedthree times with 5% KHSO₄. The aqueous layers were back-extracted oncewith EtOAc and the pooled EtOAc layers were dried (Na₂ SO₄), filteredand stripped to afford a yellow oil. The oil was dissolved in Et₂ O,cooled to 0° C. and treated with excess diazomethane for 15 minutes. Theexcess diazomethane was destroyed by the addition of HOAc and thesolvent was removed in vacuo. The residue was chromatographed (flash,Merck SiO₂, 40% acetone in hexane followed by 7:3 acetone:hexane) toafford the title compound (1.060 gm, 90%) as a colorless oil.

TLC: R_(f) 0.34 (1:1--acetone:hexane)

H.(S)-4-[[[5-Ethyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A solution of the part G compound (1.039 gm, 1.93 mmol) in dioxane (8ml) was treated with 1N NaOH (7.0 ml, 7.0 mmol) at room temperature andthe mixture was subsequently heated at 65° C. under argon for 1.5 hours.The solvent was evaporated and the residue was chromatographed on HP-20resin, eluting in succession with H₂ O (200 ml), 50% MeOH in H₂ O (200ml), and MeOH (200 ml). The desired fractions were pooled and evaporatedand the residue was taken up in H₂ O and lyophilized to give Example 59(910 mg, 80%) as a white solid.

TLC: R_(f) 0.15 (8:1:1--CH₂ Cl₂ :HOAc:MeOH) Analysis for C₂₈ H₂₇ FNNa₂O₅ P 1.89 H₂ O: Calc'd: C 57.24 H 5.28 N 2.38 F 3.23 P 5.27 Found: C57.17 H 4.99 N 2.45 F 3.25 P 5.51

Example 60(S)-4-[[[6-(Diphenylmethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A. 4-(4-Fluorophenyl)-1,1-diphenyl-3-buten-2-one

A mixture of 4-fluorobenzaldehyde (3.54 gm, 28.5 mmol) and1,1-diphenylacetone (5.000 gm, 23.8 mmol) in absolute EtOH (50 ml) wastreated with a solution of EtONa in EtOH (21% solution, 900 μl, 2.4mmol). After stirring at room temperature for 22 hours, the mixture wasconcentrated to 35 ml and the solution was treated with HOAc (200 mg).The solution was cooled to 0° C. and the precipitate that had formed wascollected by filtration and washed with cold EtOH. The title compoundwas obtained as a pale yellow solid (5.787 gm, 77%).

m.p. 122°-124° C. TLC: R_(f) 0.32 (20% EtOAc in hexane)

B.β-(4-Fluorophenyl)-α-(2-methyl-1-oxopropyl)-Δ-oxo-epsilonphenylbenzenehexanoicacid, ethyl ester

A slurry of the part A compound (5.531 gm, 17.5 mmol) and ethylisobutyrylacetate (4.220 gm, 26.7 mmol) in absolute EtOH (100 ml) wastreated with a solution of EtONa in EtOH (21% by weight solution, 980μl, 2.6 mmol). After stirring at room temperature for 4 hours, anadditional 3.0 ml of EtONa solution was added. After stirring at roomtemperature for 28 hours, the mixture was treated with HOAc (1.14 gm),cooled to 0° C. and the precipitate was collected by filtration. Thesolid was washed with cold EtOH and hexane, then dried to give the titlecompound (5.858 gm, 71%) as a single diastereomer.

m.p. 130°-131° C. TLC: R_(f) 0.20 (20% EtOAc in hexane)

C.4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(diphenylmethyl)-3-pyridinecarboxylicacid, ethyl ester

A mixture of the part B compound (5.590 gm, 11.8 mmol), NH₄ OAc (2.724gm, 35.3 mmol), and Cu(OAc)₂ (5.89 gm, 29.5 mmol) in glacial HOAc (32ml) was gently refluxed for 18 hours. The solution was cooled to roomtemperature and subsequently poured into an ice cold mixture ofconcentrated NH₄ OH (50 ml) in H₂ O (100 ml). The mixture was extractedwith Et₂ O and the Et₂ O extract was washed with H₂ O (twice) and brine,then dried (Na₂ SO₄), filtered and stripped to yield a cloudyorange-brown oil. The oil was chromatographed (flash, Merck SiO₂, 10%EtOAc in hexane) to afford the title compound (3.600 gm, 71%) as ayellow oil.

TLC: R_(f) 0.49 (20% EtOAc in hexane)

D.4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(diphenylmethyl)-3-pyridinemethanol

A cold (0° C.) solution of the ester from part C (3.562 gm) in dry THF(100 ml) was treated with LiAlH₄ (950 mg, 25 mmol). Ten minutes afterthe addition, the cooling bath was removed and the mixture was stirredat room temperature for two hours. Additional LiAlH₄ (390 mg, 10.3 mmol)was added and the mixture was stirred for one more hour. The darksolution was recooled to 0° C. and quenched in succession with H₂ O (1.5ml), 10% NaOH (1.5 ml), and H₂ O (4.5 ml). The solution was filtered andthe salts were washed with EtOAc. Removal of the solvent afforded anoil, which was chromatographed (flash, Merck SiO₂, 10% EtOAc in hexane)to give recovered starting material (1.319 gm) and the crude alcoholtitle compound (1.4 gm). The crude alcohol (an oil) was triturated withhexane to give a solid. Recrystallization from hot Et₂ O/hexane providedthe title compound (895 mg, 26%) as a pale yellow solid.

m.p. 138.5°-140° C. TLC: R_(f) 0.26 (20% EtOAc in hexane)

E.4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(diphenylmethyl)-3-pyridinecarboxaldehyde

A -78° C. solution of oxalyl chloride (230 ul, 335 mg, 2.6 mmol) in CH₂Cl₂ (10 ml) was treated dropwise with a solution of dry DMSO (400 μl,440 mg, 5.6 mmol) in CH₂ Cl₂ (1 ml). After 12 minutes, a solution ofalcohol from part D (851 mg, 2.07 mmol) in CH₂ Cl₂ (3 ml) was addeddropwise to the above mixture. Twenty minutes after the addition, TEA(1.5 ml) was added and the mixture was stirred at -78° C. for 10 minutesand then warmed to room temperature. The mixture was diluted with Et₂ Oand washed twice with H₂ O and once with brine. The organic layer wasdried (Na₂ SO₄), filtered, and stripped to yield a liquid/solid mixture.The residue was flashed (Merck SiO₂, 10% EtOAc in hexane) affording anoily solid that was recrystallized from hot hexane. The aldehyde titlecompound was obtained as a pale yellow solid (810 mg, 96%).

m.p. 101°-102° C. TLC: R_(f) 0.50 (20% EtOAc in hexane)

F.3-(2,2-Dibromoethenyl)-4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(diphenylethyl)pyridine

A solution of carbon tetrabromide (1.039 gm, 3.13 mmol) in CH₂ Cl₂ (3ml) was added over a 5-minute period to a cold (-5° C.) solution of thealdehyde from part E (802 mg, 1.96 mmol) and triphenylphosphine (1.636gm, 6.24 mmol) in CH₂ Cl₂ (10 ml). After the addition was complete, themixture was stirred at room temperature for 30 minutes. The solution wasquenched with saturated NaHCO₃ and extracted twice with CH₂ Cl₂. Thecombined organic layers were dried (Na₂ SO₄), filtered and concentrated.The concentrate was chromatographed (flash, Merck SiO₂, 30% CH₂ Cl₂ inhexane followed by CH₂ Cl₂) to give the dibromide title compound as asolid. Recrystallization of the solid from hot CH₂ Cl₂ /hexane gave theproduct (1.000 gm, 90%) as white needles.

mp 141°-142° C. TLC: R_(f) 0.42 (10% EtOAc in hexane) Microanalysis forC₂₉ H₂₄ Br₂ FN: Calc'd: C 61.61H 4.28 N 2.48 Found C 61.65 H 4.25 N 2.51

G.3-(1-Ethynyl)-4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(diphenylmethyl)pyridine

A -78° C. solution of the dibromide from part F (981 mg, 1.74 mmol) inTHF (8 ml) was treated rapidly with a solution of n-BuLi (2.5M inhexanes, 2.15 ml, 5.4 mmol). A very dark black-red solution developed.After 45 minutes, the solution was quenched with saturated NH₄ Cl(solution turned yellow), warmed to room temperature, and extracted withEt₂ O. The Et₂ O extract was washed with brine, dried (Na₂ SO₄),filtered and stripped to give an oil. The oil was flashed twice (MerckSiO₂, first in 2.5% EtOAc in hexane and then in 1% EtOAc in hexane) toyield a foam, which was triturated with hexane to give a solid. Thesolid was recrystallized from hot hexane to afford the title compound(450 mg, 64%) as an off-white solid.

m.p. 106.5°-107.5° C. TLC: Rf 0.36 (10% EtOAc in hexane)

H.(S)-4-[[[6-(Diphenylmethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methylester

Meanwhile, a solution of the acetylene from part G (445 mg, 1.1 mmol) inTHF (8 ml) at -78° C. was treated with n-BuLi (1.6M in hexane, 760 μl,1.22 mmol) over a 1-minute period. The acetylenic anion solution wasadded dropwise via cannula over a 5-minute period to a -78° C. solutionof the phosphonochloridate from Example 57, part G, in THF (6 ml). Theresulting mixture was stirred at -78° C. for 30 minutes then quenchedwith 50% saturated NH₄ Cl. The solution was warmed to 0° C., dilutedwith H₂ O, and poured into saturated NaHCO₃. The aqueous phase wasextracted once with Et₂ O. The Et₂ O layer was washed with brine, dried(Na₂ SO₄), filtered and stripped to give a yellow oil. The residue waschromatographed (flash, Merck SiO₂, 40% EtOAc in hexane) to afford thetitle compound as an oily foam (329 mg, 36%).

TLC: R_(f) 0.26 (40% EtOAc in hexane)

I.(S)-4-[[[6-(Diphenylmethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methylester

A mixture of the part H compound (314 mg, 0.38 mmol),tetra-n-butylammonium fluoride (1.0M in THF, 1.10 ml, 1.10 mmol), andHOAc (86 ul, 95 mg, 1.6 mmol) in THF (4 ml) was stirred at roomtemperature for 17 hours. The solution was diluted with EtOAc and washedthree times with 5% KHSO₄. The EtOAc layer was washed with brine, dried(Na₂ SO₄), filtered and stripped to afford a yellow oil. The oil wasdissolved in Et₂ O, cooled to 0° C. and treated with excess diazomethanefor 20 minutes. The excess diazomethane was destroyed by the addition ofHOAc and the solvent was removed vacuo. The residue was chromatographed(flash, Merck SiO₂, 40% acetone in hexane followed by 1:1acetone:hexane) to afford the title compound (189 mg, 84%) as acolorless oil.

TLC: R_(f) 0.34 (1:1--acetone:hexane)

J.(S)-4-[[[6-(Diphenylmethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A solution of the part I compound (178 mg, 0.30 mmol) in dioxane (3.5ml) was treated with 1N NaOH (1.1 ml, 1.1 mmol) at room temperature andthe mixture was subsequently heated at 58° C. under argon for 1.5 hours.The solvent was evaporated and the residue was chromatographed on HP-20resin, eluting in succession with H₂ O (150 ml), 50% MeOH in H₂ O (200ml), and 100% MeOH (100 ml). The desired fractions were pooled andevaporated and the residue was taken up in H₂ O and lyophilized to giveExample 60 (171 mg, 88%) as a white solid.

TLC: R_(f) 0.16 (8:1:1--CH₂ Cl₂ :HOAc:MeOH) Analysis for C₃₃ H₂₉ FNNa₂O₅ P * 2.0 H₂ O: Calc'd: C 60.83 H 5.11N 2.15 F 2.92 P 4.75 Found: C60.80 H 4.82 N 2.09 F 2.93 P 4.56

Example 61(S)-4-[[6-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A. 1-(4-Fluorophenyl)-4,4-dimethyl-1-penten-3-one

A mixture of 4-fluorobenzaldehyde (12.13 ml, 110 mmol, Aldrich) andpinacolone (12.48 ml, 100 mmol, Aldrich) in absolute ethanol (120 ml)was treated with a solution of sodium ethoxide in ethanol (21% by weightsolution; 3.72 ml, 10 mmol). The clear yellow reaction mixture wasstirred at room temperature under argon for 24 hours. The reactionmixture was concentrated to 1/3volume and partitioned between 50%saturated NH₄ Cl and EtOAc. The layers were separated and the organiclayer was washed twice with H₂ O and brine, then dried (Na₂ SO₄) andconcentrated under reduced pressure. The oily residue was purified byflash chromatography (Merck Silica gel, 10% EtOAc/hexane), yielding thetitle compound as a colorless oil that slowly solidified. The whitesolid was recrystallized from hexane, yielding the title compound aswhite crystals (13.9 g, 67.5%).

R_(f) 0.62 (30% EtOAc/hexane), UV Analysis for C₁₃ H₁₅ FO: Calc'd: C,75,70; H, 7.33 Found: C, 75.46; H, 7.23

B.3-(4-Fluorophenyl)-6,6-dimethyl-2-(2-methyl-1-oxopropyl)-5-oxoheptanoicacid, ethyl ester

A mixture of the part A compound (13.02 g, 63.2 mmol) and ethylisobutyrylacetate (10.00 g, 63.2 mmol) in absolute ethanol (150 ml) wastreated with a solution of sodium ethoxide in ethanol (21% by weightsolution, 2.43 ml, 6.32 mmol). After 6 hours, additional sodium ethoxide(0.2 equiv) was added and the reaction mixture was stirred overnight.The reaction mixture was concentrated to 1/3 volume and partitionedbetween 50% saturated NH₄ Cl and EtOAc. The layers were separated andthe organic layer was washed twice with H₂ O and brine, dried (Na₂ SO₄)and concentrated under reduced pressure. The oily residue was dissolvedin hot hexane and cooled. The precipitated material was collected byfiltration (17.1 g, 74.0%; mixture of diastereomers) to afford the titlecompound as a white solid.

m.p. 80°-89° C. R_(f) 0.44+0.40 (20% EtOAc/hexane), UV Analysis for C₂₁H₂₉ FO₄ : Calc'd: C, 69.21; H, 8.02; F, 5.21 Found: C, 69.12; H, 8.06;F, 5.03

C.6-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinecarboxylicacid, ethyl ester

A mixture of the part B compound (17.0 g, 46.65 mmol), ammonium acetate(10.78 g, 139.95 mmol) and copper (II) acetate (23.28 g, 116.62 mmol) inglacial acetic acid (125 ml) was heated at 110° C. for 16 hours. Thesolution was cooled to room temperature and poured into an ice coldmixture of concentrated NH₄ OH (150 ml) and H₂ O (200 ml). The mixturewas extracted with ether (twice) and the ether extracts were washed withH₂ O (twice) and brine, then dried (MgSO₄), filtered and concentrated togive an oily residue. Purification by flash chromatography (Merck Silicagel, 5% EtOAc/hexane) afforded the title compound as a colorless oil(12.5 g, 78.0%).

R_(f) 0.72 (15% EtOAc/hexane), UV

D.6-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinemethanol

A cold (0° C.) solution of the ester prepared in part C (12.5 g, 36.39mmol) in dry THF (200 ml) was treated with LiAlH₄ (4.14 g, 109.17 mmol).Ten minutes after the addition the cooling bath was removed and thereaction mixture was stirred at room temperature for 2 hours. Thereaction mixture was cooled to 0° C. and carefully quenched by dropwiseaddition of 4.2 ml of H₂ O in THF (25 ml), then 4.2 ml 15% NaOH andfinally 8.0 ml H₂ O. The precipitated aluminum salts were filtered andwashed with EtOAc and ether. The filtrate was washed with H₂ O andbrine, dried (Na₂ SO₄), filtered and concentrated under reducedpressure. The solid residue was recrystallized from hexane, yielding thetitle compound as a white solid (9.3 g, 85.0%).

m.p. 112°-113° C. R_(f) 0.47 (15% EtOAc/hexane), UV Analysis for C₁₉ H₂₄NFO: Calc'd: C, 75.71; H, 8.03; N, 4.65; F, 6.30 Found: C, 75.77; H,8.01; N, 4.63; F, 6.08

E.6-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinecarboxaldehyde

A -78° C. solution of oxalyl chloride (3.10 ml, 35.78 mmol) in CH₂ Cl₂(100 ml) was treated dropwise with a solution of dry DMSO (5.08 ml,71.56 mmol) in CH₂ Cl₂ (10 ml). After 15 minutes, a solution of thealcohol from part D (9.0 g, 29.82 mmol) in CH₂ Cl₂ (50 ml) was addeddropwise to the above solution. After 20 minutes, triethylamine (25.0ml, 179.0 mmol) was added and the mixture was stirred at -78° C. for 20minutes and then warmed to room temperature. After 1 hour, the reactionwas quenched with H₂ O and diluted with ether. The layers were separatedand the aqueous layer was extracted with ether (twice). The combinedorganic solutions were washed with H₂ O (twice) and brine, dried(MgSO₄), filtered and concentrated under reduced pressure. The dark oilyresidue was purified by flash chromatography (5% EtOAc/hexane) yieldingthe title compound as a colorless oil (6.95 g, 78.0%).

R_(f) 0.60 (20% EtOAc/hexane), UV

F.3-(2,2-Dibromoethenyl)-6-(1,1-dimethylethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)pyridine

A solution of carbon tetrabromide (4.97 g, 15.0 mmol) in CH₂ Cl₂ (15 ml)was added dropwise over a 5-minute period to a cold (0° C.) solution ofthe aldehyde from part E (3.00 g, 10.0 mmol) and triphenylphosphine(7.08 g, 127 mmol) in CH₂ Cl₂ (60 ml). The mixture was stirred at 0° C.for 10 minutes and then at room temperature for 30 minutes. The solutionwas quenched with saturated NaHCO₃ and extracted twice with CH₂ Cl₂. Thecombined organic layers were dried (Na₂ SO₄), filtered, concentrated to1/3 volume and applied on Merck silica gel column (50% CH₂ Cl₂ /hexane).Flash chromatography afforded the product as a colorless viscous oilwhich slowly solidified into an off-white solid. Recrystallization fromhot hexane afforded the dibromide title compound as a white solid (3.95g, 86.8%).

m.p. 98°-100° C. R_(f) 0.56 (15% EtOAc/hexane), UV

G.(S)-4-[[6-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methylester

A solution of the dibromide from part F (3.80 g, 8.34 mmol) in THF (10ml) at -78° C. was treated with n-BuLi (2.5M in hexane, 7.00 ml, 17.51mmol) over a 1-minute period. The dark-blue reaction mixture was stirredfor 1 hour at -78° C. and then transferred via cannula to a -78° C.solution of the phosphonochloridate from Example 57, part G, in THF (10ml). The green-brown reaction mixture was stirred at -78° C. for 30minutes and quenched with 50% saturated NH₄ Cl. After warming to roomtemperature, the solution was diluted with H₂ O and poured intosaturated NaHCO₃. The layers were separated and the aqueous layer wasextracted once with ether. The combined organic layers were washed withbrine, dried (Na₂ SO₄), filtered and concentrated under reducedpressure. The dark oily residue was purified by flash chromatography(Merck silica gel, 30% EtOAc/hexane) to afford the title compound as apale yellow foam (3.85 g, 64.2%).

R_(f) 0.20 (30% EtOAc/hexane), UV

H.(S)-4-[[6-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methylester

To a solution of the acetylinic phosphonate of part G (3.75 g, 5.13mmol) in THF (25 ml) was added HOAc (1.17 ml, 20.52 mmol), followed bytetra-n-butylammonium fluoride (1.0M in THF, 15.39 ml, 15.39 mmol). Thereaction mixture was stirred at room temperature under argon for 24hours. The solution was diluted with EtOAc and washed three times with5% KHSO₄. The aqueous layer was back-extracted twice with EtOAc and thecombined organic extracts were dried (Na₂ SO₄), filtered andconcentrated under reduced pressure. The yellow-orange oil was dissolvedin ether (with a few drops of THF added to obtain a clear solution),cooled to 0° C. and treated with excess diazomethane for 30 minutes. Theexcess diazomethane was destroyed by the addition of HOAc. Solventremoval gave a dark oily residue, which was purified by flashchromatography (Merck silica gel, 40% EtOAc/hexane). The title compoundwas obtained as a colorless oil (0.24 g, 37.0%).

R_(f) 0.41 (50% acetone/hexane) UV

I.(S)-4-[[6-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

The diester from part H (1.50 g, 3.06 mmol) in dioxane (5 ml) wastreated with 1N NaOH (10.70 ml, 10.7 mmol) at room temperature and thenheated at 50° C. for 2.5 hours. The solvent was evaporated and theresidue was chromatographed on HP-20 resin, eluting first with H₂ O (200ml), followed by 25% MeOH/H₂ O (300 ml), 50% MeOH/H₂ O (500 ml) andfinally MeOH (100ml). The collected product fractions were evaporated,dissolved in H₂ O, filtered, frozen and lyophilized to give Example 61as a white lyophilate (0.22 g, 80.5%).

R_(f) 0.25 (8:1:1--CH₂ Cl₂ :CH₃ OH:HOAc), UV Analysis for C₂₄ H₂₇ NFPO₅Na₂ ×1.17 H₂ O: Calc'd: C, 54,76; H, 5.62; N, 2.66; F, 3.61; P, 5.88Found: C, 54.69; H, 5.69; N, 2.73; F, 3.44; P, 5.59

Example 62(S)-4-[[[4-(4-Fluorophenyl)-6-(1-naphthalenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A. 3-(4-Fluorophenyl)-1-(1-naphthalenyl)-2-propen-1-one

A mixture of 4-fluorobenzaldehyde (6.40 ml, 60.0 mmol, Aldrich) and1'-acetonaphtone (10.21 g, 60.0 mmol, Aldrich) in glacial HOAc (100 ml)and concentrated H₂ SO₄ (8.75 ml) was stirred under argon at roomtemperature for 2 days. The dark yellow-red reaction mixture was cooledto 0° C. and poured into an ice cold mixture of concentrated NH₄ OH/H₂ O(150/225 ml). The mixture was extracted with ether (3×200 ml) and thecombined ether extracts were washed with H₂ O (three times), saturatedNaHCO₃ (twice), and brine, then dried (Na₂ SO₄), filtered andconcentrated. The dark oily residue was distilled (0.5 mm Hg, bp 30° C.)to remove unreacted 4-fluorobenzaldehyde. The pot residue was purifiedby flash chromatography (Merck silica gel, 1% ether/toluene). Theproduct was obtained as a dark yellow oil (18.0 g) which by NMR showedabout 30% contamination with acetonaphtone.

R_(f) 0.27 (20% EtOAc/hexane), UV, visually yellow

B.β-(4-Fluorophenyl)-α-(2-methyl-1-oxopropyl)-Δ-oxo-1-naphthalenepentanoicacid, ethyl ester

A mixture of the part A compound (9.80 g, 35.67 mmol) and ethylisobutyrylacetate (8.63 ml, 53.51 mmol) in absolute ethanol (120 ml) wastreated with a solution of sodium ethoxide in ethanol (21% by weightsolution, 1.97 ml, 5.35 mmol). The reaction mixture was stirred for 12hours then concentrated to 1/3 volume and partitioned between 50%saturated NH₄ Cl and EtOAc. The layers were separated and the organiclayer was washed twice with H₂ O and brine, then dried (Na₂ SO₄) andconcentrated under reduced pressure. The oily residue was dissolved inhot hexane and cooled. The precipitate was collected by filtration togive the title compound as a white solid (6.9 g, 47.0%; mixture ofdiastereomers).

m.p. 103°-105° C. R_(f) 0.34+0.39 (20% EtOAc/hexane), UV Analysis forC₂₇ H₂₇ FO₄ : Calc'd: C, 74.63; H, 6.26; F, 4.37 Found: C, 74.70; H,6.26; F, 4.25

C.4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(1-naphthalenyl)-3-pyridinecarboxylicacid, ethyl ester

A mixture of the part B compound (7.50 g, 17.29 mmol), ammonium acetate(4.00 g, 51.87 mmol) and copper (II) acetate (8.62 g, 43.22 mmol) inglacial acetic acid (50 ml) was heated at 110° C. for 12 hours. Thesolution was cooled to room temperature and poured into an ice coldmixture of concentrated NH₄ OH (70 ml) and H₂ O (100 ml). The mixturewas extracted with ether (twice) and the ether extracts were washed withH₂ O (twice) and brine, then dried (MgSO₄), filtered and concentrated togive a yellow oily residue. Purification by flash chromatography (MerckSilica gel, 15% EtOAc/hexane) afforded the title compound as a paleyellow oil which solidified on standing under high vacuum (5.1 g,71.8%). An analytical sample was recrystallized from hexane, yieldingthe product as a white crystalline material.

m.p. 113°-115° C. R_(f) 0.42 (15% EtOAc/hexane), UV Analysis for C₂₇ H₂₄NFO₂ : Calc'd: C, 78.34; H, 5.85; N, 3.39; F, 4.59 Found: C, 78.50; H,5.85; N, 3.33; F, 4.54

D.4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(1-naphthalenyl)-3-pyridinemethanol

A cold (0° C.) solution of the ester from part C (4.90 g, 11.85 mmol) indry THF (60 ml) was treated with LiAlH₄ (1.35 g, 35.55 mmol). Tenminutes after the addition, the cooling bath was removed and thereaction mixture was stirred at room temperature for 1.5 hours. Thereaction mixture was cooled to 0° C. and quenched by dropwise additionof 1.35 ml of H₂ O in THF (15 ml), then 1.35 ml 15% NaOH, and finally2.7 ml H₂ O. The precipitated aluminum salts were filtered and washedwith EtOAc and ether. The filtrate was washed with H₂ O and brine, thendried (Na₂ SO₄), filtered and concentrated under reduced pressure. Thesolid residue was recrystallized from hexane yielding the title compoundas a white solid (3.9 g, 88.6%).

m.p. 73°-75° C. R_(f) 0.34 (20% EtOAc/hexane), UV Analysis for C₂₅ H₂₂NFO: Calc'd: C, 80.84; H, 5.97; N, 3.77; F, 5.11 Found: C, 80.74; H,6.07; N, 3.55; F, 4.96

E.4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(1-naphthalenyl)-3-pyridinecarboxaldehyde

A -78° C. solution of oxalyl chloride (1.05 ml, 12.00 mmol) in CH₂ Cl₂(60 ml) was treated dropwise with a solution of dry DMSO (1.70 ml, 24.00mmol) in CH₂ Cl₂ (5 ml). After 15 minutes, a solution of the alcoholfrom part D (3.71 g, 10.00 mmol) in CH₂ Cl₂ (25 ml) was added dropwiseto the above solution. After 20 minutes, triethylamine (8.36 ml, 60.00mmol) was added and the mixture was stirred at -78° C. for 20 minutesand then warmed to room temperature. After 1 hour, the reaction wasquenched with H₂ O and diluted with ether. The layers were separated andaqueous layer was extracted with ether (twice). The combined organicsolutions were washed with H₂ O (twice) and brine, dried (MgSO₄),filtered and concentrated under reduced pressure. The off-white solidresidue was recrystallized from EtOAc/hexane yielding the title compoundas an off-white solid (2.9 g, 78.0%).

m.p. 128°-129° C. R_(f) 0.52 (20% EtOAc/hexane), UV Analysis for C₂₅ H₂₀NFO: Calc'd: C, 81.28; H, 5.46; N, 3.79; F, 5.14 Found: C, 79.92; H,5.71; N, 3.98; F, 5.01

F.3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-6-(1-naphthalenyl)-3-pyridine

A solution of carbon tetrabromide (3.90 g, 11.75 mmol) in CH₂ Cl₂ (10ml) was added dropwise over a 5-minute period to a cold (0° C.) solutionof the aldehyde from part E (2.90 g, 7.85 mmol) and triphenylphosphine(6.17 g, 23.55 mmol) in CH₂ Cl₂ (60 ml). The mixture was stirred at 0°C. for 10 minutes and then at room temperature for 30 minutes. Thesolution was quenched with saturated NaHCO₃ and extracted twice with CH₂Cl₂. The combined organic layers were dried (Na₂ SO₄), filtered,concentrated to 1/3 volume and applied on Merck silica gel column (50%CH₂ Cl₂ /hexane). Flash chromatography afforded the title compound as acolorless viscous oil which became a foam upon drying in vacuo (3.90 g,95.1%).

R_(f) 0.58 (15% EtOAc/hexane), UV

G.(S)-4-[[[4-(4-Fluorophenyl)-6-(1-naphthalenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

A solution of the dibromide from part F (3.80 g, 7.23 mmol) in THF (10ml) at -78° C. was treated with n-BuLi (2.5M in hexane, 6.07 ml, 15.18mmol) over a 1-minute period. The dark-blue reaction mixture was stirredfor 1 hour at -78° C. and then transferred via cannula to a -78° C.solution of the phosphonochloridate from Example 57, part G, in THF (10ml). The green-brown reaction mixture was stirred at -78° C. for 30minutes and quenched with 50% saturated NH₄ Cl. After warming to roomtemperature, the solution was diluted with H₂ O and poured intosaturated NaHCO₃. The layers were separated and the aqueous wasextracted once with ether. The combined organic layers were washed withbrine, dried (Na₂ SO₄), filtered and concentrated under reducedpressure. The dark oily residue was purified by flash chromatography(Merck silica gel, 30% EtOAc/hexane) to afford the title compound as apale yellow foam (2.65 g, 62.1%).

R_(f) 0.13 (30% EtOAc/hexane), UV

H.(S)-4-[[[4-(4-Fluorophenyl)-6-(1-naphthalenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

To a solution of the acetylinic phosphonate from part G (2.50 g, 3.12mmol) in THF (25 ml) was added HOAc (0.72 ml, 12.48 mmol), followed bytetra-n-butylammonium fluoride (1.0M in THF, 9.37 ml, 9.37 mmol). Thereaction mixture was stirred at room temperature under argon for 24hours. The solution was diluted with EtOAc and washed three times with5% KHSO₄. The aqueous layer was back-extracted twice with EtOAc and thecombined organic extracts were dried (Na₂ SO₄), filtered andconcentrated under reduced pressure. The yellow-orange oil was dissolvedin ether (with a few drops of THF to obtain a clear solution), cooled to0° C. and treated with excess diazomethane for 20 minutes. The excessdiazomethane was destroyed by the addition of HOAc. Solvent removal gavea dark oily residue, which was purified by flash chromatography (Mercksilica gel, 40% acetone/hexane). The title compound was obtained as apale yellow oil (1.08 g, 62.1%).

R_(f) 0.32 (50% acetone/hexane) UV

I.(S)-4-[[[4-(4-Fluorophenyl)-6-(1-naphthalenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

The diester from part H (1.00 g, 1.78 mmol) in dioxane (5 ml) wastreated with 1N NaOH (6.25 ml, 6.25 mmol) at room temperature and thenheated at 50° C. for 2.5 hours. The solvent was evaporated and theresidue was chromatographed on HP-20 resin, eluting first with H₂ O (200ml), followed by 25% MeOH/H₂ O (250 ml), 50% MeOH/H₂ O (250 ml) andfinally with MeOH (100 ml). The collected product fractions wereevaporated, dissolved in H₂ O, filtered, frozen and lyophilized to giveExample 62 as a white lyophilate (0.84 g, 82.3%).

R_(f) 0.27 (8:1:1--CH₂ Cl₂ :CH₃ OH:HOAc), UV Analysis for C₃₀ H₂₅ NFPO₅Na₂ ×1.22 H₂ O: Calc'd: C, 60.31; H, 4.63; N, 2.34; F, 3.18; P, 5.18Found: C, 60.22; H, 4.78; N, 2.43; F, 3.15; P, 4.98

Example 63(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)benzo[6,7]cyclohepta[1,2-b]pyridin-3-yl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A.β-(4-Fluorophenyl)-6,7,8,9-tetrahydro-α-(2-methyl-1-oxopropyl)-5-oxo-5H-benzocycloheptene-6-propanoicacid, ethyl ester

A -78° C. solution of LiN(TMS)₂ (1.0M in THF, 27.5 ml, 27.5 mmol) andTHF (15 ml) was treated with a solution of benzosuberone (6.000 gm, 22.7mmol) in THF (3 ml) over a 1-minute period. After 60 minutes, a solutionof the compound from Example 53, part A (4.08 gm, 15.4 mmol) in THF (3ml) was added dropwise to the above solution. The mixture was stirred at-78° C. for 30 minutes and then warmed to 0° C. After 20 minutes, themixture was quenched with HOAc (3.4 ml), diluted with saturated NH₄ Cland H₂ O and subsequently extracted with Et₂ O. The Et₂ O extract waswashed with brine, then dried (Na₂ SO₄), filtered, and stripped to yielda viscous pale yellow gum. The material was used directly in the nextreaction.

B.4-(4-Fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-benzo[6,7]cyclohepta[1,2-b]pyridine-3-carboxylicacid, ethyl ester

The aforementioned crude mixture of the compound of part A, NH₄ OAc(5.25 gm, 68.1 mmol), and Cu(OAc)₂ (11.33 gm, 57 mmol) in glacial HOAc(60 ml) was gently refluxed for 19 hours. The solution was cooled toroom temperature and subsequently poured into an ice cold mixture ofconcentrated NH₄ OH (100 ml) in H₂ O (200 ml). The mixture was extractedonce with Et₂ O the organic extract was washed with H₂ O and brine, thendried (Na₂ SO₄), filtered and stripped to yield a dark red-purple oil.The residue was flashed (Merck SiO₂, 10% EtOAc in hexane) to give theimpure title compound as an oil (6.707 gm, estimated purity of 90%).

TLC: R_(f) 0.53 (20% EtOAc in hexane)

C.4-(4-Fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-benzo[6,7]cyclohepta[1,2-b]pyridine-3-methanol

A cold (0° C.) solution of the impure ester of part B (6.692 gm) in dryTHF (200 ml) was treated with LiAlH₄ (1.910 gm, 50 mmol). The ice bathwas removed and the mixture was stirred at room temperature for 3.5hours. The solution was then cooled to 0° C. and quenched in successionwith H₂ O (2 ml), 10% NaOH (2 ml), and H₂ O (6 ml). The solution wasfiltered and the salts were washed with EtOAc and Et₂ O. The filtratewas stripped of solvent to afford a gum, which was triturated withhexane to produce a solid. The solid was recrystallized twice from hotEtOAc/hexane to provide the title compound (3.800 gm, 68% from compoundA from Example 53) as a white solid.

m.p. 160.5°-161.8° C. TLC: R_(f) 0.24 (20% EtOAc in hexane)

D.4-(4-Fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-benzo[6,7]cyclohepta[1,2-b]pyridine-3-carboxaldehyde

A -78° C. solution of oxalyl chloride (630 ul, 917 mg, 7.2 mmol) in CH₂Cl₂ (40 ml) was treated dropwise with a solution of dry DMSO (1.10 ml,1.21 gm, 15.5 mmol) in CH₂ Cl₂ (1 ml). After 10 minutes, a solution ofthe alcohol from part C (2.000 gm, 5.5 mmol) in THF (5 ml) was addeddropwise to the above mixture. Fifteen minutes after the addition, TEA(4.6 ml) was added and the mixture was stirred at -78° C. for 5 minutesand then warmed to room temperature. The mixture was diluted with Et₂ Oand washed twice with H₂ O and once with brine. The organic layer wasdried (Na₂ SO₄), filtered, and stripped to give a yellow oil, whichsolidified upon cooling to -78° C. in hexane. The mixture was thencrystallized from hot hexane to give the aldehyde title compound (1.775gm, 89%) as white needles.

m.p. 132°-134° C. TLC: R_(f) 0.54 (20% EtOAc in hexane)

E.(3-(2,2-Dibromoethenyl)-4-(4-Fluorophenyl)-6,7-dihydro-2-(1-methylethyl)benzo[6,7]cyclohepta[1,2-b]pyridine

A solution of carbon tetrabromide (2.336 gm, 7.0 mmol) in CH₂ Cl₂ (6 ml)was added over a 7-minute period to a cold (0° C.) solution of thealdehyde from part D (1.688, 4.7 mmol) and triphenylphosphine (3.698 gm,14.1 mmol) in CH₂ Cl₂ (20 ml). After the addition was complete, thecooling bath was removed and the mixture was stirred at room temperaturefor 25 minutes. The solution was quenched with saturated NaHCO₃ andextracted twice with CH₂ Cl₂. The organic layers were dried (Na₂ SO₄),filtered and concentrated. The concentrate was chromatographed (flash,Merck SiO₂, 40% CH₂ Cl₂ in hexane) to give the dibromide title compoundas a solid. Recrystallization of the material from hot EtOAc/hexaneprovided the pure title compound (2.257 gm, 93%) as a white solid.

m.p. 173°-175° C. TLC: R_(f) 0.44 (10% EtOAc in hexane) Microanalysisfor C₂₅ H₂₂ Br₂ FN: Calc'd: C 58.27 H 4.30 N 2.72 F 3.69 Br 31.02 Found:C 58.27 H 4.29 N 2.69 F 3.62 Br 31.35

F.(S)-4-[[[4-(4-fluorophenyl)-2-(1-methylethyl)-benzo[6,7]cyclohepta[1,2-b]-pyridin-3-yl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

Meanwhile, a solution of the dibromide from part E (2.000 gm, 3.88 mmol)in THF (10 ml) at -78° C. was treated with n-BuLi (2.5M in hexane, 3.3ml, 8.2 mmol) over a 1-minute period, and the resulting clear greensolution was stirred at -78° C. for 50 minutes. The acetylenic anionsolution was added dropwise via cannula over a 10-minute period to a-78° C. solution of the phosphonochloridate from Example 57, part G inTHF (12 ml). The resulting mixture was stirred at -78° C. for 30minutes, then quenched with 50% saturated NH₄ Cl. The solution waswarmed to 0° C. and poured into saturated NaHCO₃. The aqueous phase wasextracted once with Et₂ O. The Et₂ O layer was washed with brine, dried(Na₂ SO₄), filtered and stripped to give an oil. The residue waschromatographed (flash, Merck SiO₂, 40 % EtOAc in hexane) to afford thetitle compound as a colorless foam (2.517 gm, 82%).

TLC: R_(f) 0.31 (40% EtOAc in hexane)

G.(S)-4-[[[4-(4-fluorophenyl)-2-(1-methylethyl)-benzo[6,7]cyclohepta[1,2-b]-pyridin-3-yl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

A mixture of the part F compound (2.487 gm, 3.15 mmol),tetra-n-butylammonium fluoride (1.0M in THF, 11.0 ml, 11.0 mmol), andHOAc (810 ul, 850 mg, 14.1 mmol) in THF (40 ml) was stirred at roomtemperature for 18 hours. The solution was diluted with EtOAc and washedthree times with 5% KHSO₄ and once with brine. The EtOAc layer was dried(Na₂ SO₄), filtered and stripped to afford a yellow oil. The oil wasdissolved in Et₂ O, cooled to 0° C. and treated with excess diazomethanefor 10 minutes. The excess diazomethane was destroyed by the addition ofHOAc and the solvent was removed in vacuo. The residue waschromatographed (flash, Merck SiO₂, 40% acetone in hexane) to afford thetitle compound (1.534 gm, 89%) as a colorless foam.

TLC: R_(f) 0.38 (1:1--acetone:hexane)

H.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-benzo[6,7]cyclohepta[1,2-b]-pyridin-3-yl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A solution of the part G compound (780 mg, 1.42 mmol) in dioxane (7 ml)was treated with 1N NaOH (5.0 ml, 5.0 mmol) and the mixture was stirredat room temperature for 18 hours. The solvent was evaporated and theresidue was chromatographed on HP-20, eluting in succession with H₂ O(200 ml), 50% MeOH in H₂ O (200 ml), and MeOH (100 ml). The desiredfractions were pooled and evaporated and the residue was taken up in H₂O and lyophilized to give Example 63 (744 mg, 90%) as a white solid.

TLC: R_(f) 0.17 (8:1:1--CH₂ Cl₂ :HOAc:MeOH) Analysis for C₂₉ H₂₇ FNNa₂O₅ P×0.80 H₂ O: C 60.06 H 4.97 N 2.42 F 3.28 P 5.34 Found: C 59.98 H5.02 N 2.50 F 3.52 P 5.55

Example 64(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-[2-(phenylmethyl)phenyl]-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A. 2'-(Phenylmethyl)acetophenone

Oxalyl chloride (4.1 ml, 47 mmol) was added to a solution of2-(phenylmethyl)benzoic acid (from Aldrich) in methylene chloride (100ml) over 5 minutes at room temperature. The solution was allowed to stirat room temperature for 2 hours. The solution was concentrated and theresultant orange gum azeotroped with benzene (twice) and placed underhigh vacuum for 1 hour. In a separate flask, methyl lithium (1.4M inTHF, 100 ml, 140 mmol) was added over 10 minutes to a slurry of CuI₂(13.432 gm, 42.3 mmole) in ether (125 ml). The slurry was allowed tostir for 2 minutes. The above-prepared acid chloride in ether (50 ml) at-78° C. was cannulated over 20 minutes into the dimethyl lithiumcupratesolution, which was also cooled to -78° C. The solution stirred for anadditional 20 minutes, then was quenched with methanol (30 ml) andwarmed to room temperature. The solution was then added to saturated NH₄Cl (200 ml), and the aqueous layer was extracted with ether (twice). Theorganic layers were combined and washed with brine, then dried overMgSO₄, filtered and concentrated to afford an orange oil. The crude oilwas purified by flash chromatography on Merck silica gel in 5% EtOAc inhexane. The fractions containing the product were combined andconcentrated to afford the title compound as a pale yellow solid (3.090gm, 63%).

m.p. 42°-43° C. TLC: Rf 0.39 (5% EtOAc in hexane)

B. 3-(4-Fluorophenyl)-1-[2-(phenylmethyl)phenyl-2-propen-1-one

A solution of sodium ethoxide (21% by weight in EtOH, 0.100 gm, 1.47mmol) was added to a solution of compound 2 (3.090 gm, 14.7 mmol) and4-fluorobenzaldehyde (2.00 gm, 16.2 mmol) in ethanol (100 ml), which wasstirring under argon at room temperature. The solution was allowed tostir 18 hours and then was concentrated to afford an orange oil. Thecrude oil was dissolved in hexane and ether and, upon cooling, affordedthe title compound as a yellow crystalline solid (2.30 gm, 86%).

m.p. 76°-78° C. TLC: Rf 0.24 (5% EtOAc in hexane) Elemental Analysis forC₂₂ H₁₇ FO* 0.11 H₂ O: Calc'd: C 83.02 H 5.45 F 5.97 Found: C 83.02 H5.42 F 5.78

C.β-(4-Fluorophenyl-α-(2-methyl-1-oxopropyl)-γ-oxo-2-(phenylmethyl)benzenepentanoicacid, ethyl ester

A solution of sodium ethoxide (21% by weight in EtOH, 0.192 gm, 2.8mmol) was added to a slurry of the ethyl isobutyrylacetate from part B(4.480 gm, 28 mmol) and the enone from part B (6.015 gm, 19 mmol) inethanol (100 ml), which was stirring under argon at room temperature.The slurry was allowed to stir 16 hours. Then, ethanol (30 ml) was addedto the flask to make a slurry of the reaction mixture, which hadpartially solidified. Then, acetic acid (0.343 gm, 5.71 mmol) was addedto the reaction mixture, and a white solid was filtered out of solution.The solid was dried under high vacuum for 2 hours to afford the titlecompound as a pure, white solid (8.220 gm, 92%).

m.p. 120°-122° C. TLC: Rf 0.49 (20% EtOAc in hexane) Elemental Analysisfor C₃₀ H₃₁ FO* 2.89 H₂ O: Calc'd: C 75.28 H 7.75 F 3.97 Found: C 75.28H 6.69 F 3.98

D.4-(4-Fluorophenyl)-2-(1-methylethyl)-6-[2-(phenylmethyl)phenyl]-3-pyridinecarboxylicacid, ethyl ester

NH₄ OAc (4.00 gm, 52 mmol) and Cu(OAc)₂ (3.63 gm, 43.25 mmol) were addedto an acetic acid solution (50 ml) of the 1,5 diketone from part C(8.220 gm, 17.3 mmol). The solution was allowed to reflux for 18 hoursunder argon. The solution was then poured into an ice-cold solution ofNH₄ OH/H₂ O (100 ml/100 ml). The mixture was extracted with ether(twice), washed with water and saturated NaCl, then dried over Na₂ SO₄and concentrated to afford an orange oil, which solidified uponstanding. The orange solid was purified by flash chromatography on Mercksilica gel in 15% EtOAc in hexane. Those fractions containing theproduct were pooled and evaporated to give the title compound as aslightly orange solid (5.220 gm, 67%).

m.p. 94°-97° C. TLC: Rf 0.64 (20% EtOAc in hexane) Elemental analysisfor C₃₀ H₂₈ NFO: Calc'd: C 79.44 H 6.22 N 3.09 F 4.19 Found: C 79.45 H6.01 N 3.02 F 4.27

E.4-(4-Fluorophenyl)-2-(1-methylethyl)-6-[2-(phenylmethyl)phenyl]-3-pyridinemethanol

A THF solution (50 ml) of the ester from part D (5.220 gm, 11.5 mmol)was cooled to 0° C. and treated with LiAlH₄ (1.31 gm, 34.5 mmol). Thesolution stirred 17 hours, then was cooled to 0° C. and quenched bydropwise addition of 1.3 ml of water followed by 1.3 ml of 15% NaOH,then 3.9 ml water. The aluminum paste was filtered out of solution andthe filtrate concentrated to give a yellowish solid. The solid wasrecrystallized from EtOAc and hexane to afford the title compound aslarge clear crystals (3.043 gm, 65%).

m.p. 122°-124° C. TLC: Rf 0.08 (10% EtOAc in hexane) Elemental Analysisfor C₂₈ H₂₄ NFO* 0.78 H₂ O: Calc'd: C 79.41 H 6.08 N 3.30 F 4.49 Found:C 79.42 H 6.03 N 3.30 F 4.48

F.4-(4-Fluorophenyl)-2-(1-methylethyl)-6-[2-(phenylmethyl)phenyl]-3-pyridinecarboxaldehyde

A solution of DMSO (0.993 gm, 12.71 mmol) in THF (5 ml) was added tooxalyl chloride (0.807 gm, 6.36 mmol) in THF (35 ml) at -78° C. underargon. The solution stirred 20 minutes, then the alcohol from part E(2.000 gm, 4.89 mmol) was added dropwise as a THF (10 ml) solution.Twenty-five minutes later, triethyl amine (3.65 ml, 26 mmol) was addedto the reaction mixture. The solution was stirred for 20 minutes andthen was warmed to room temperature. The solution was diluted with etherand washed with water and brine, then dried over Na₂ SO₄, filtered andconcentrated to afford a yellowish solid. The solid was purified byflash chromatography on Merck silica gel in 3-5% EtOAc in hexane.Fractions containing the product were combined and concentrated. Theresultant white solid was recrystallized from hexane to give the titlecompound as white crystals (1.380 gm, 69%).

m.p. 205°-207° C. TLC: Rf 0.53 (20% EtOAc in hexane)

G.3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-6-[2-(phenylmethyl)phenyl]-3-pyridine

A solution of CBr₄ (1.68 gm, 5.06 mmol) in methylene chloride solution(25 ml) was added over 20 minutes to a solution of triphenyl phosphine(2.83 gm, 10.78 mmol) and the aldehyde from part F (1.38 gm, 3.37 mmol)in methylene chloride (25 ml), which was stirring under argon at 0° C.The solution stirred for an additional 45 minutes. Then, saturatedNaHCO₃ (15 ml) was added to quench the reaction. The solution was thenallowed to warm to room temperature. The aqueous layer was extractedwith methylene chloride (twice) and the organic layers combined andwashed with brine, then dried over Na₂ SO₄, filtered concentrated toabout 10 ml. The solution was subjected to flash chromatography on Mercksilica gel in 20% methylene chloride in hexane. Pure fractions werepooled and concentrated to afford the title compound as a white foam(1.71 gm, 90%).

TLC: Rf 0.73 (10% EtOAc in hexane)

H.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-[2-(phenylmethyl)phenyl]-3-pyridinyl]ethynyl]-methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methylester

n-BuLi (2.5M in hexane, 2.3 ml, 5.66 mmol) was added dropwise to asolution of the dibromide from part G (1.60 gm, 2.83 mmol) in THF (20ml) at -78° C. under argon. The solution was allowed to stir 1 hour at-78° C., then cannulated into a THF solution (15 ml) of the chloridatefrom Example 57, part G, which had also been cooled to -78° C. Theresultant orange solution was stirred for 30 minutes, then quenched withsaturated NH₄ Cl (15 ml) and warmed to 0° C. Saturated NaHCO₃ was thenadded to the solution. After warming to room temperature, the mixturewas diluted with ether. The organic layer was washed with brine, driedover Na₂ SO₄, filtered and concentrated to give an orange oil. The oilwas purified by flash chromatography on Merck silica gel in 40% EtOAc inhexane. Pure product fractions were combined and evaporated to affordthe title compound as a beige foam (1.37 gm, 58%).

TLC: Rf 0.53 (50% ETOAc in hexane)

I.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-[2-(phenylmethyl)phenyl]-3-pyridinyl]ethynyl]-methoxyphosphinyl]-3-hydroxybutanoicacid, methylester

(Bu)₄ NF (1.0M in THF, 4.8 ml, 4.8 mmol) was added to a solution of thesilyl ether from part H (1.375 gm, 1.60 mmol) and acetic acid (0.387 gm,6.4 mmol) in THF (10 ml) and allowed to stir 25 hours at roomtemperature. The solution was diluted with EtOAc (20 ml) and washed with5% KHSO₄ (three times). The aqueous layers were extracted with EtOAc(twice). The organic layers were pooled and washed with brine, thendried over Na₂ SO₄, filtered and concentrated to afford a pale yellowoil. The oil was dissolved in ether (15 ml) and treated with excess CH₂N₂. Excess CH₂ N₂ was removed with a stream of argon, and the solutionwas concentrated to a yellow oil. The oil was purified by flashchromatography on Merck silica gel in 40% acetone in hexane. Pureproduct fractions were pooled and concentrated to afford the titlecompound as a beige foam (0.735 gm, 78%).

TLC: Rf 0.34 (40% acetone in hexane)

J.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-[2-(phenylmethyl)phenyl]-3-pyridinyl]ethynyl]-hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

The part I (0.545 gm, 0.93 mmol) was dissolved in dioxane (10 ml) andtreated with NaOH (1M in water, 2.31 ml, 2.3 mmol). The solution wasthen heated to 55° C. for 1 hour. The mixture was concentrated to ayellowish solid. The solid was dissolved in water and chromatographed onHP-20 resin, eluting first with water (200 ml) and then with 50% MeOH inwater (400 ml). The desired fractions were pooled and concentrated andthe resultant residue was taken up in water and lyophilized to giveExample 64 as a fluffy white solid (0.550 gm, 99%).

TLC: Rf 0.62 (6:3:1, n-propanol:NH₄ OH:water) Elemental Analysis for C₃₃H₂₉ NFNa₂ PO₅ * 1.24 H₂ O: Calc'd: C 62.14 H 4.97 N 2.20 F 2.98 Found: C62.02 H 5.05 N 2.32 F 3.02

Example 65(S)-4-[[[4-(4-Fluorophenyl)-2,5-bis(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A. (3-Methyl-1-methylenebutyl)benzene

Chloro-(2-methylpropyl)magnesium (150 ml, 0.300 mol, from Aldrich) wasadded over 20 minutes to a solution of benzonitrile (10.21 ml, 0.100mol, from Aldrich) in ether (150 ml), stirring under argon at roomtemperature. The solution was allowed to stir under argon at roomtemperature for 18 hours. The reaction mixture was then cooled to 0° C.and 1.2N HCl (125 ml) was added. The aqueous layer was extracted withether (twice), and the organic layers were combined and washed withbrine and dried over MgSO₄, filtered and concentrated to a yellow oil.The oil was purified by flash chromatography on Merck silica gel in 2%EtOAc in hexane. Fractions containing the product were combined andconcentrated to afford the title compound as a yellow oil (13.305 gm,83%).

TLC: Rf 055 (5% EtOAc in hexane)

B.β-(4-Fluorophenyl)-γ-(1-methylethyl)-α-(2-methyl-1-oxopropyl)-Δ-oxobenzenepentanoicacid, ethyl ester

A THF solution (3 ml) of the ketone from part A (5.0 gm, 0.031 mol) wasadded over 5 minutes to a solution of LiN(TMS)₂ (30.9 ml, 0.031 ml) inTHF (17 ml), which was stirring under argon at -78° C. The solution wasallowed to stir 1 hour and 45 minutes at -78° C. A solution of theβ-keto ester from Example 53, part A (6.79 gm, 0.257 mol) in THF (5 ml)was then added over 5 minutes. The solution was warmed to 0° C. andstirred for 1 hour and 30 minutes. The reaction mixture was quenchedwith acetic acid. Then saturated NH₄ Cl (100 ml) was added to thesolution. The aqueous layer was extracted with ether (twice), theorganic layers were combined and washed with brine, then dried over Na₂SO₄, filtered and concentrated to give a yellow oil. Purification of theoil was achieved by flash chromatography on Merck silica gel in 5% EtOAcin hexane. Fractions containing the product were combined andconcentrated to afford the title compound as a clear oil (7.760 gm,57%).

TLC: Rf 0.20 and 0.23 (20% EtOAc in hexane)

C.4-(4-Fluorophenyl)-2,5-bis(1-methylethyl)-6-phenyl-3-pyridinecarboxylicacid, ethyl ester

NH₄ OAc (4.202 gm, 54.5 mmol) and Cu(OAc)₂ (8.635 g, 43.25 mmol) wereadded to an acetic acid solution (50 ml) of 1,5 diketone B (7.760 gm,18.2 mmol). The solution was allowed to reflux 18 hours under argon. Thesolution was then poured into an ice-cold solution of NH₄ OH/H₂ O (100ml/100 ml). The mixture was extracted with ether (twice), washed withwater and saturated NaCl, then dried over Na₂ SO₄, and concentrated toafford an orange oil which solidified upon standing. The solid waspurified by flash chromatography on Merck silica in 15% EtOAc in hexane.Fractions containing the pure product were pooled and concentrated. Theresultant white solid was recrystallized from EtOAc and hexane to affordthe title compound as fine white needles (3.341 gm, 45%).

m.p. 138°-140° C. TLC: Rf 0.55 (10% EtOAc in hexane) Elemental analysisfor C₂₆ H₃₂ NFO₂ : Calc'd: C 76.25 H 7.88 N 3.42 F 4.64 Found: C 76.90 H6.98 N 3.53 F 4.74

D. 4-(4-Fluorophenyl)-2,5-bis(1-methylethyl)-6-phenyl-3-pyridinemethanol

A THF solution (50 ml) of the ester from part C (3.214, 7.9 mmol) wascooled to 0° C. and treated with LiAlH₄ (0.902 gm, 23.77 mmol). Thesolution was allowed to stir 18 hours. The solution was then cooled to0° C. and quenched by dropwise addition of 0.9 ml of water followed by0.9 ml of 15% NaOH, then 2.7 ml water. The aluminum paste was filteredout of solution and the filtrate concentrated to a white solid.Recrystallization of the solid from EtOAc and hexane afforded the titlecompound as fluffy white needles (2.277 gm, 79%).

m.p. 244°-246° C. TLC: Rf 0.13 (20% EtOAc in hexane) Elemental Analysisfor C₂₄ H₂₈ NFO* 0.14 H₂ O: Calc'd: C 78.33 H 7.75 N 3.81 F 5.16 Found:C 78.29 H 7.10 N 3.85 F 5.16

E.4-(4-Fluorophenyl)-2,5-bis(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyd

A solution of DMSO (0.84 gm, 10.68 mmol) in CH₂ Cl₂ (1 ml) was added toa solution of oxalyl chloride (0.321 ml, 3.68 mmol) in CH₂ Cl₂ (35 ml)cooled to -78° C. under argon. After stirring 15 minutes, the alcoholfrom part D (1.025 gm, 2.83 mmol) was added dropwise to the flask as aTHF/CH₂ Cl₂ (9 ml/5 ml) solution. Twenty-five minutes later, triethylamine (2.9 ml, 21 mmol) was added to the reaction mixture. The solutionstirred for 20 minutes and then was warmed to room temperature. Thesolution was diluted with ether and washed with water and brine, thendried over Na₂ SO₄, filtered and concentrated to afford a white solid.The white solid was recrystallized from hexane to give the titlecompound as white, lumpy crystals (0.866 gm, 85%).

m.p. 159°-160° C. TLC: Rf 0.53 (20% EtOAc in hexane) Elemental Analysisfor C₂₄ H₂₄ NFO×0.07 H₂ O: Calc'd: C 79.48 H 6.71 N 3.86 F 5.24 Found: C79.68 H 6.58 N 3.68 F 5.33

F.3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-2,5-bis(1-methylethyl)-6-phenylpyridine

A solution of CBr₄ (1.185 gm, 3.57 mmol) in methylene chloride (7 ml)was added over 20 minutes to a solution of triphenylphosphine (1.87 gm,7.14 mmol) and the aldehyde from part E (0.866 gm, 2.38 mmol) inmethylene chloride (20 ml), which was stirring under argon at 0° C. Thesolution stirred for an additional twenty minutes, at 0° C., then waswarmed to room temperature and stirred 30 minutes. The reaction was thenquenched with saturated NaHCO₃. The aqueous layer was extracted withmethylene chloride (twice), the organic layers were combined and washedwith brine, then dried over Na₂ SO₄, filtered and concentrated to about5 ml. The solution was purified by flash chromatography on Merck silicagel in 30% methylene chloride in hexane. Pure fractions were pooled andconcentrated to afford the title compound as a white foam (1.178 gm,97.5%).

TLC: Rf 0.69 (20% EtOAc in hexane)

G.(S)-4-[[[4-(4-Fluorophenyl)-2,5-bis(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

N-BuLi (2.5M in hexane, 1.84 ml, 4.6 mmol) was added dropwise to asolution of the dibromide from part F (1.178 gm, 2.3 mmol) in THF (20ml) at -78° C. under argon. The solution was allowed to stir 1 hour at-78° C., then cannulated into a THF solution (30 ml) of the chloridatefrom Example 57, part G which had also been cooled to -78° C. Theresultant orange solution was stirred 1 hour, then quenched withsaturated NH₄ Cl (15 ml). The solution was warmed to 0° C. and thensaturated NaHCO₃ was added to the flask. The mixture was extracted withether (three times), the organic layers were pooled and washed withbrine, then dried over Na₂ SO₄, filtered and concentrated to an amberoil. The oil was purified by flash chromatography on Merck silica gel in40% EtOAc in hexane. Pure product fractions were combined and evaporatedto afford the title compound as a beige foam (0.950 gm, 52%).

TLC: Rf 0.53 (50% ETOAc in hexane)

H.(S)-4-[[[4-(4-Fluorophenyl)-2,5-bis(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

(Bu)₄ NF (1M in THF, 3.55 ml, 3.55 mmol) was added to the silyl etherfrom part G (0.948 gm, 1.194 mmol) and acetic acid (0.284 gm, 4.73 mmol)in THF (10 ml). The solution was allowed to stir 19 hours at roomtemperature. Additional (Bu)₄ NF (1M in THF, 236 ml, 2.36 mmol) and HOAc(0.19 gm, 3.16 mmol) was added to the solution which was allowed to stir2 more hours. The mixture was diluted with EtOAc and washed with 5%KHSO₄ (three times). The aqueous layers were extracted with EtOAc(twice), the organic layers were combined and washed with brine, thendried over Na₂ SO₄, filtered and concentrated to give an orange oil. Theoil was dissolved in ether and treated with excess CH₂ N₂. Excess CH₂ N₂was removed by bubbling argon through the solution. The solution wasconcentrated to give a yellow oil. The oil was purified by flashchromatography on Merck silica gel in 40% acetone in hexane. Fractionscontaining the product were combined and concentrated to afford thetitle compound as a white foam (0.496 gm, 81%).

TLC: Rf 0.22 (40% acetone in hexane)

I.(S)-4-[[[4-(4-Fluorophenyl)-2,5-bis(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

The alcohol from part H was dissolved in dioxane (10 ml) and treatedwith a solution of NaOH (1M in water, 2.31 ml, 2.3 mmol). The solutionwas heated to 55° C. for 1.5 hours. Additional NaOH (1M in water, 1.0ml, 1.0 mmol) was added to the solution which was allowed to stir onemore hour at 55° C. The solution was then concentrated to a yellowishsolid which was dissolved in water and chromatographed on HP-20 resin,eluting first with water (200 ml) and then with 50% MeOH in water (400ml). The desired fractions were pooled and concentrated. The resultantresidue was taken up in water and lyophilized to give Example 65 as afluffy white solid (0.310 gm, 94%).

TLC: Rf 0.62 (6:3:1, n-propanol:NH₄ OH:water) Elemental Analysis for C₂₉H₂₉ NFNa₂ PO₅ * 2.78 H₂ O: Calc'd: C 56.40 H 5.64 N 2.27 F 3.08 Found: C56.44 H 5.72 N 2.23 F 3.16

Example 66(S)-4-[[[6-(1-Adamantyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A. 1-(1-Adamantyl)-3-(4-fluorophenyl)-2-propen-1-one

A mixture of 4-fluorobenzaldehyde (6.01 ml, 56.10 mmol, Aldrich) and1-adamantyl methyl ketone (10.00 g, 56.10 mmol) in absolute ethanol (100ml) was treated with a solution of sodium ethoxide in ethanol (21% byweight solution; 2.08 ml, 5.61 mmol). A precipitate soon fell out ofsolution. After stirring at room temperature for 48 hours, the mixturewas cooled to -10° C. and the precipitate was collected by filtration.The solid was washed with cold ethanol, dried in vacuo andrecrystallized from hexane. The title compound was obtained as anoff-white solid (9.20 g, 57.8%).

m.p. 126°-127° C. R_(f) 0.55 (25% EtOAc/hexane), UV Analysis for C₁₉ H₂₁FO: Calc'd C, 80.25; H, 7.44; F, 6.68 Found C, 79.43; H, 7.54; F, 6.94

B. (4-Fluorophenyl)-α-(2-methyl-1-oxopropyl)-Δ-oxo-1-adamantanepentanoicacid, ethyl ester

A mixture of the part A compound (9.10 g, 32.00 mmol) and ethylisobutyrylacetate (7.75 ml, 48.00 mmol) in absolute ethanol (120 ml) wastreated with a solution of sodium ethoxide in ethanol (21% by weightsolution, 5.95 ml, 16.00 mmol). The reaction mixture was stirred for 48hours. The obtained heavy suspension was cooled to -10° C., filtered andthe off-white solids were washed with cold EtOH. The crude product wasrecrystallized from hot hexane, affording the title compound as anoff-white solid (10.6 g, 74.8%, mixture of diastereomers).

m.p. 104°-105° C. R_(f) 0.42+0.44 (20% EtOAc/hexane), UV Analysis forC₂₇ H₃₅ FO₄ : Calc'd C, 73.27; H,7.97; F, 4.29 Found C, 72.87; H,7.93;F, 4.25

C.1-(1-Adamantyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinecarboxylicacid,ethyl ester

A mixture of the part B compound (10.50 g, 23.70 mmol), ammonium acetate(5.48 g, 71.10 mmol) and copper (II) acetate (11.83 g, 59.25 mmol) inglacial acetic acid (75 ml) was heated at 110° C. for 16 hours. Thesolution was cooled to room temperature and poured into an ice coldmixture of concentrated NH₄ OH (100 ml) and H₂ O (150 ml). The mixturewas extracted with ether (twice) and the ether extracts were washed withH₂ O (twice) and brine, then dried (MgSO₄), filtered and concentratedinto an oily residue that became a white hard foam upon drying in vacuo(high) (10.0 g, 100.0%). The crude title compound was used directly forthe next reaction.

R_(f) 0.61 (20% EtOAc/hexane), UV

D.1-(1-Adamantyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinemethanol

A cold (0° C.) solution of the ester from part C (10.0 g, 23.70 mmol) indry THF (100 ml) was treated with LiAlH₄ (2.70 g, 71.17 mmol). Tenminutes after the addition the cooling bath was removed and the reactionmixture stirred at room temperature for 2.5 hours. The reaction mixturewas cooled to 0° C. and while stirring, carefully quenched by thedropwise addition of 2.7 ml of H₂ O in THF (15 ml), then 2.7 ml of 15%NaOH and finally 5.4 ml H₂ O. The precipitated aluminum salts werefiltered and washed with EtOAc and ether. The filtrate was washed withH₂ O and brine, dried (Na₂ SO₄), filtered and concentrated under reducedpressure to give an oily residue. Purification by flash chromatography(Merck silica gel, 5% EtOAc/hexane) yielded the title compound as awhite solid, which was recrystallized from hot hexane (6.7 g, 74.6%).

m.p. 143°-145° C. R_(f) 0.34 (20% EtOAc/hexane), UV Analysis for C₂₅ H₃₀NFO: Calc'd C, 79.12; H, 7.97; N, 3.69; F, 5.01 Found C, 79.03; H, 8.25;N, 3.77; F, 4.90

E.1-(1-Adamantyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinecarboxaldehyde

A -78° C. solution of oxalyl chloride (1.85 ml, 21.21 mmol) in CH₂ Cl₂(150 ml) was treated dropwise with a solution of dry DMSO (3.01 ml,42.40 mmol) in CH₂ Cl₂ (25 ml). After 15 minutes, a solution of thealcohol from part D (6.70 g, 17.67 mmol) in CH₂ Cl₂ (50 ml) was addeddropwise to the above solution. After 20 minutes, triethylamine (14.78ml, 106.02 mmol) was added and the mixture was stirred at -78° C. for 20minutes and then warmed to room temperature. After 1.5 hours, thereaction was quenched with H₂ O and diluted with ether. The layers wereseparated and aqueous layer was extracted with ether (twice). Thecombined organic extracts were washed with H₂ O (twice) and brine, dried(MgSO₄), filtered and concentrated under reduced pressure. The oilyresidue was purified by flash chromatography (Merck silica gel, 5%EtOAc/hexane) to give the aldehyde title compound as a white solid. Thesolid was recrystallized from hexane yielding the title compound aswhite crystals (5.5 g, 83.5%).

m.p. 109°-110° C. R_(f) 0.66 (20% EtOAc/hexane), UV Analysis for C₂₅ H₂₈NFO: Calc'd C, 79.54; H, 7.48; N,3.71; F, 5.03 Found C, 79.25; H, 7.32;N,3.61; F, 4.80

F. 1-(1-Adamantyl)-3-(2,2-dibromoethenyl)-2-(1-methylethyl)pyridine

A solution of carbon tetrabromide (2.63 g, 7.95 mmol) in CH₂ Cl₂ (10 ml)was added dropwise over a 5-minute period to a cold (0° C.) solution ofthe aldehyde from part E (2.00 g, 5.30 mmol) and triphenylphosphine(4.17 g, 15.90 mmol) in CH₂ Cl₂ (60 ml). The mixture was stirred at 0°C. for 10 minutes and then at room temperature for 30 minutes. Thesolution was quenched with saturated NaHCO₃ and extracted twice with CH₂Cl₂. The combined organic layers were dried (Na₂ SO₄), filtered,concentrated to 1/3 volume and applied on Merck silica gel column (50%CH₂ Cl₂ /hexane). Flash chromatography afforded the title compound as awhite solid, which was recrystallized from hexane (2.3 g, 82.1%).

m.p. 176°-177° C. R_(f) 0.65 (15% EtOAc/hexane), UV

G.(S)-4-[[[6-(1-Adamantyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

A solution of the dibromide from part F (2.2 g, 4.13 mmol) in THF (18ml) at -78° C. was treated with n-BuLi (2.5M in hexane, 3.46 ml, 8.67mmol) over a minute period. The green-blue reaction mixture was stirredfor 45 minutes at -78° C. and then transferred via cannula to -78° C.solution of the phosphonochloridate from Example 57, part G, in THF (10ml). The green-brown reaction mixture was stirred at -78° C. for 30minutes and quenched with 50% saturated NH₄ Cl. After warming to roomtemperature, the solution was diluted with H₂ O and poured intosaturated NaHCO₃. The layers were separated and the aqueous layer wasextracted once with ether. The combined organic layers were washed withbrine, dried (Na₂ SO₄), filtered and concentrated under reducedpressure. The dark oily residue was purified by flash chromatography(Merck silica gel, 15% EtOAc/hexane) to afford the title compound as acolorless oil (1.95 g, 59.0%).

R_(f) 0.36 (30% EtOAc/hexane), UV

H.(S)-4-[[[6-(1-Adamantyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

To a solution of the acetylinic phosphonate of part G (1.9 g, 2.36 mmol)in THF (15 mmol) was added HOAc (0.53 ml, 9.44 mmol), followed bytetra-n-butylammonium fluoride (1.0M in THF, 7.08 ml, 7.08 mmol). Thereaction mixture was stirred at room temperature under argon for 24hours. The solution was diluted with EtOAc and washed three times with5% KHSO₄. The aqueous layer was back-extracted twice with EtOAc and thecombined organic extracts were dried (Na₂ SO₄), filtered andconcentrated under reduced pressure. The yellow-orange oil was dissolvedin ether (added a few drops of THF to obtain a clear solution), cooledto 0° C. and treated with excess diazomethane in ether for 20 minutes.The excess diazomethane was destroyed by the addition of HOAc. Solventremoval gave a dark oily residue, which was purified by flashchromatography (Merck silica gel, 20% acetone/hexane). The titlecompound was obtained as a colorless oil (0.69 g, 60.0%).

R_(f) 0.59 (40% acetone/hexane) UV

I.(S)-4-[[[6-(1-Adamantyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

The diester from part H (0.69 g, 1.21 mmol) in dioxane (15 ml) wastreated with 1N NaOH (4.23 ml, 4.23 mmol) at room temperature and thenheated at 50° C. for 2.5 hours. The reaction mixture became opaque anddioxane was added until a clear solution was obtained (30 ml). Afterheating for an additional 16 hours the reaction mixture again becameopaque with oily droplets present. To obtain a clear solution, MeOH (15ml) was added and the solution was treated with additional 1N NaOH(1.21ml) and heated for 4 hours. Solvent was evaporated and the residuewas chromatographed on HP-20 resin, eluting first with H₂ O (300 ml),followed by 25% MeOH/H₂ O (300 ml), 50% MeOH/H₂ O (300 ml) and finallyMeOH (100 ml). The collected product fractions were evaporated,dissolved in H₂ O, filtered, frozen and lyophilized to yield Example 66as a white lyophilate (0.30 g, 48.0%).

R_(f) 0.45 (8:1:1--CH₂ Cl₂ :CH₃ OH:HOAc), UV Analysis for C₃₀ H₃₃ NFPO₅Na₂ ×2.0 H₂ O: Calc'd C, 58.15; H,6.02; N,2.26; F, 3.07; P,5.00 Found C,58.24; H,5.77; N,2.11; F, 3.04; P,4.79

Example 67(S)-4-[[[5-Fluoro-4-(4-fluorophenyl)-2-(1-methylethyl))-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A. 2-Fluoroacetophenone

A mixture of 2-bromoacetophenone (20.00 gm, 100 mmol) and KF (8.82 gm,152 mmol) in dry DMF (35 ml) was heated at 100° C. for 1 hour.Additional KF (2.26 gm) was added and heating of the mixture continuedfor 4 more hours. The dark-red solution was cooled, poured into Et₂ Oand washed with H₂ O (twice) and brine. The ethereal solution was dried(Na₂ SO₄), filtered, and stripped to yield a dark red oil. The oil wasdistilled to collect a fraction boiling between 62°-64° C. at 1 mm Hgwhich was 91 molar percent the title compound and 9 molar percentacetophenone (6.00 gm). Flash chromatography (Merck SiO₂, 10% EtOAc inhexane) afforded the pure title compound (5.50 gm, 45%) as a liquid thatsolidifies near room temperature.

TLC R_(f) 0.28 (20% EtOAc in hexane)

B.Δ-Fluoro-β-(4-fluorophenyl)-α-(2-methyl-1-oxopropyl)-.DELTA.-oxobenzenepentanoicacid, ethyl ester

A -78° C. solution of LiN(TMS)₂ (1.0M in THF, 28.7 ml, 28.7 mmol) in dryTHF (17 ml) was treated with a solution of 2-fluoroacetophenone (A)(3.500 gm, 28.65 mmol) in THF (3 ml). After 50 minutes, a solution oftitle compound from Example 53, part A, (6.310 gm, 23.9 mmol) in THF (4ml) was added dropwise to the above solution. After 1.25 hours, thered-orange mixture was quenched with saturated NH₄ Cl and warmed to roomtemperature. The mixture was diluted with H₂ O and subsequentlyextracted with Et₂ O. The Et₂ O extract was washed with brine, dried(Na₂ SO₄), filtered, and stripped to give a yellow oil containing thetitle compound in crude form.

C.5-Fluoro-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxylicacid, ethyl ester

A mixture of the above crude oil, NH₄ OAc (5.52 gm, 71.6 mmol), andCu(OAc)₂ (16.77 gm, 84 mmol) in glacial HOAc (80 ml) was heated at 100°C. for 2 hours. Additional NH₄ OAc (2.5 gm) was added and thetemperature of the reaction mixture was raised to 110° C. and heatingcontinued for 16 hours. The solution was cooled to room temperature andsubsequently poured into an ice cold mixture of concentrated NH₄ OH (90ml) in H₂ O (120 ml). The mixture was extracted with Et₂ O and the Et₂ Oextract was washed with H₂ O and brine, then dried (Na₂ SO₄), filteredand stripped to yield a brown oil. The oil was flashed (Merck SiO₂, 5%EtOAc in hexane) to give the title compound as a colorless oil (1.190gm, approx. 11%), which was contaminated with an undetermined amount ofthe non-5-fluorinated pyridine ester4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxylic acid,ethyl ester.

TLC R_(f) 0.49 (20% EtOAc in hexane)

D.5-Fluoro-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinemethanol

A cold (0° C.) solution of the ester from part C (purity uncertain,2.875 gm, assume 7.5 mmol) in dry THF (80 ml) was treated with LiAlH₄(990 mg, 26 mmol). After the addition, the temperature of the reactionwas raised to 25° C. and stirring of the mixture continued for 2 hours.The solution was recooled to 0° C. and quenched in succession with H₂ O(1 ml), 10% NaOH (1.5 ml), and H₂ O (3 ml). The solution was filteredand the salts were washed with EtOAc. The filtrate was stripped to yielda mixture of the title compound and the non-fluorinated pyridine alcohol(the title compound where F on the pyridine ring is replaced with H) asa solid that could not be purified by recrystallization. The solid wasdissolved in warm 40% EtOAc in hexane and flashed twice (Merck SiO₂, 20%EtOAc in hexane) to give the title compound (approx. 90% purity, 800 mg)and impure title compound (approx. 60% purity, 682 mg) as solids.

m.p. 163.5°-165° C. TLC R_(f) 0.19 (20% EtOAc in hexane)

E.5-Fluoro-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde

A -78° C. solution of oxalyl chloride (435 μl, 633 mg, 5.0 mmol) in CH₂Cl₂ (15 ml) was treated dropwise with a solution of dry DMSO (710 μl,782 mg, 10.0 mmol) in CH₂ Cl₂ (1 ml). After 15 minutes, a solution ofthe alcohol from part D (91% purity, 1.300 gm, assume 3.83 mmol) in CH₂Cl₂ (5 ml) and THF (2 ml) was added dropwise to the above mixture.Twenty minutes after the addition, TEA (3.4 ml) was added and themixture was stirred at -78° C. for 5 minutes and then warmed to roomtemperature. The mixture was diluted with Et₂ O and washed twice with H₂O and once with brine. The organic layer was dried (Na₂ SO₄), filtered,and stripped to yield a solid. The solid was dissolved in CH₂ Cl₂ andflashed (Merck SiO₂, 5% EtOAc in hexane) to give the desired product inapproximately 92% purity. Recrystallization from hexane gave in twocrops the title compound (1.153 gm, 89%) which was pure by NMR analysis.

m.p. 135.5°-137.2° C. TLC R_(f) 0.45 (20% EtOAc in hexane)

F.3-(2,2-Dibromoethenyl)-5-fluoro-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridine

A solution of carbon tetrabromide (1.579 gm, 4.8 mmol) in CH₂ Cl₂ (6 ml)was added over a 10-minute period to a cold (0° C.) solution of thealdehyde from part E (1.070 gm, 3.17 mmol) and triphenylphosphine (2.500gm, 9.5 mmol) in CH₂ Cl₂ (15 ml). After the addition was complete, thecooling bath was removed and the mixture was stirred for 30 minutes. Thesolution was quenched with saturated NaHCO₃ and extracted twice with CH₂Cl₂. The combined organic layers were dried (Na₂ SO₄), filtered andconcentrated. The concentrate was chromatographed (flash, Merck SiO₂,30% CH₂ Cl₂ in hexane) to give the dibromide title compound as a whitefoam that solidified. Recrystallization from hexane gave the titlecompound (1.321 gm, 84%) as a white solid.

m.p. 104.5°-107.0° C. TLC R_(f) 0.54 (20% EtOAc in hexane)

G.(S)-4-[[[5-Fluoro-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

A solution of the dibromide from part F (1.230 gm, 2.49 mmol) in THF (8ml) at -78° C. was treated with n-BuLi (2.5M in hexane, 2.5 ml, 6.25mmol) over a 15-second period and the resulting dark brown-red solutionwas stirred for 40 minutes. The acetylenic anion solution was addeddropwise via cannula over a 10-minute period to a -78° C. solution ofthe phosphonochloridate from Example 57, part G in THF (12 ml). Theresulting mixture was stirred at -78° C. for 30 minutes, then quenchedwith 50% saturated NH₄ Cl. The solution was warmed to 0° C., dilutedwith H₂ O, and poured into saturated NaHCO₃. The aqueous phase wasextracted once with Et₂ O. The Et₂ O layer was washed with brine, dried(Na₂ SO₄), filtered and stripped to give an orange oil. The residue waschromatographed (flash, Merck SiO₂, 40% EtOAc in hexane) to afford thetitle compound as a yellow foam (1.254 gm, 66%).

TLC R_(f) 0.29 (40% EtOAc in hexane)

H.(S)-4-[[[5-Fluoro-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

A mixture of the part G compound (1.227 gm, 1.60 mmol),tetra-n-butylammonium fluoride (1.0M in THF, 6.4 ml, 6.4 mmol), and HOAc(400 ul, 420 mg, 7 mmol) in THF (14 ml) was stirred at room temperaturefor 16 hours. The solution was diluted with EtOAc and washed 3 timeswith 5% KHSO₄. The EtOAc layer was dried (Na₂ SO₄), filtered andstripped to afford an oil. The oil was dissolved in Et₂ O, cooled to 0°C. and treated with excess diazomethane for 5 minutes. The excessdiazomethane was destroyed by the addition of HOAc and the solvent wasremoved in vacuo. The residue was chromatographed (flash, Merck SiO₂,30% acetone in hexane followed by 40% acetone in hexane) to afford thetitle compound (669 mg, 79%) as a colorless oil.

TLC R_(f) 0.38 (1:1--acetone:hexane)

I.(S)-4-[[[5-Fluoro-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A solution of the part H compound (412 mg, 0.78 mmol) in dioxane (5 ml)was treated with 1N NaOH (2.8 ml, 2.8 mmol) at room temperature and themixture was subsequently heated at 60° C. under argon for 1.5 hours. Thesolvent was evaporated and the residue was chromatographed on HP-20resin, eluting in succession with H₂ O (200 ml), 50% MeOH in H₂ O (200ml), and MeOH (100 ml). The desired fractions were pooled and evaporatedand the residue was taken up in H₂ O and lyophilized to give Example 67(343 mg, 76%) as a white solid.

TLC R_(f) 0.13 (8:1:1--CH₂ Cl₂ :HOAc:MeOH) Analysis for C₂₆ H₂₂ F₂ Na₂NO₅ P×1.79 H₂ O: C, 54.25; H, 4.48; N, 2.43; F, 6.60; P, 5.38 Found: C,54.23; H, 4.04; N, 2.45; F, 6.28; P, 5.33

Example 68 (S)-4-[[[4-(4-Fluorophenyl)-2,6-bis(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A. 1-(4-Fluorophenyl)-4-methyl-1-penten-3-one

A sodium ethoxide solution (21% by weight in EtOH, 4.86 gm, 15 mmol) wasadded to a mixture of methylisopropylketone (8.61 gm, 100 mmol, fromAldrich) and 4-fluorobenzaldehyde (12.411 gm, 100 mmol, from Aldrich) inethanol (150 ml). The solution was allowed to stir at room temperaturefor 3 hours. The solvent was evaporated to afford an orange oil. The oilwas dissolved in ether, washed with saturated NH₄ Cl and brine, thendried over Na₂ SO₄, filtered and concentrated to give an orange oil. Theoil was purified by distillation (bp=106° C. at 1.3 mm Hg) to afford thetitle compound as a pale yellow oil (10.118 gm, 53%).

TLC: Rf 0.32 (5% EtOAc in hexane)

B. 3-(4-Fluorophenyl)-6-methyl-2-(2-methyl-1-oxopropyl)-5-oxoheptanoicacid, ethyl ester

A sodium ethoxide solution (21% by weight in EtOH, 3.27 gm, 10.1 mmol)was added to a mixture of ethyl isobutyrylacetate (16.03 gm, 101.1 mmol)and the enone of part A (12.944, 67.4 mmol) in ethanol (200 ml). Thesolution was allowed to stir 66 hours under argon at room temperature.The solution was then concentrated to an orange oil and partitionedbetween saturated NH₄ Cl and EtOAc. The organic layer was washed withwater and brine, dried over Na₂ SO₄, filtered and concentrated to give apale yellow oil. The oil was dissolved in boiling hexane and cooled to0° C. The title compound was obtained as fine white needles (18.352 gm,78%).

m.p. 57°-60° C. TLC: Rf 0.20 (5% EtOAc in hexane) Elemental Analysis forC₂₀ H₂₇ FO₄ : Calculated C, 68.55; H, 7.77; F, 5.42 Found C, 68.63; H,7.96; F, 5.35

C. 4-(4-Fluorophenyl)-2,6-bis(1-methylethyl)-3-pyridinecarboxylic acid,ethyl ester

NH₄ OAc (10.52, 136.5 mmol) and Cu(OAc)₂ (22.71 gm, 113.75 mmol)) wereadded to an acetic acid solution (100 ml) of the 1,5 diketone of part B(15.97 gm, 45.5 mmol). The solution was allowed to reflux 18 hours underargon, then cooled to room temperature and poured into an ice-coldsolution of NH₄ OH/H₂ O (150 ml/200 ml). The mixture was extracted withether (twice), the organic layers were pooled and washed with water andsaturated NaCl, then dried over Na₂ SO₄ and concentrated to afford ayellow oil which was used directly in the next reaction.

TLC: Rf 0.16 (10% EtOAc in hexane)

D. 4-(4-Fluorophenyl)-2,6-bis(1-methylethyl)-3-pyridinemethanol

A THF solution (150 ml) of the crude ester from part C (14.900 gm, 45mmol) was cooled to 0° C. and treated with LiAlH₄ (5.42 gm, 143 mmol).The solution was allowed to stir twenty minutes at 0° C. and then warmedto room temperature and stirred 3.5 hours. The solution was then cooledto 0° C. and quenched by dropwise addition of 5.4 ml of water, followedby 5.4 ml of 15% NaOH, then 16.2 ml water. The aluminum paste wasfiltered out of solution and the filtrate concentrated to give a yellowsolid. The solid was recrystallized from hexane to afford the titlecompound as hard yellow crystals (9.429 gm, 73% from the part Bcompound).

m.p. 88°-90° C. TLC: Rf 0.125 (10% EtOAc in hexane) Elemental Analysisfor C₁₈ H₂₂ NFO*0.08 H₂ O: Calculated C, 74.85; H, 7.73; N, 4.85; F,6.58 Found C, 75.01; H, 7.85; N, 4.69; F, 6.34

E. 4-(4-Fluorophenyl)-2,6-bis(1-methylethyl)-3-pyridinecarboxaldehyde

A solution of DMSO (5.22 gm, 66.8 mmol) in methylene chloride (20 ml)was added to a solution of oxalyl chloride (4.24 gm, 33.4 mmol) inmethylene chloride (125 ml) which had been cooled to -78° C. The alcoholfrom part D (7.350 gm, 26 mmol) was then added dropwise to the flask asa methylene chloride (25 ml) solution. Methylene chloride (25 ml) wasadded to the solution slowly in order to make a slurry out of thereaction mixture, which had solidified. Triethylamine (18.4 ml, 13.8mmol) was added 20 minutes later, and the solution was stirred for anadditional 10 minutes, then warmed to room temperature. The solution wasdiluted with ether, washed with water and brine, dried over Na₂ SO₄,filtered and concentrated to afford a yellow solid. The solid wasdissolved in hot hexane, and cooled, to give the title compound as hardyellowish crystals (5.839 gm, 79%).

m.p. 72°-75° C. TLC: Rf 0.21 (10% EtOAc in hexane)

F.3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-2,6-bis(1-methylethyl)pyridine

A solution of CBr₄ (10.30 gm, 30.5 mmol) in methylene chloride (100 ml)was added over 15 minutes to a solution of triphenylphosphine (17.140gm, 65.3 mmol) and the aldehyde from part E (5.800 g, 20.4 mmol) inmethylene chloride (150 ml), which was stirring under argon at 0° C. Thesolution stirred for an additional 45 minutes at 0° C., then at roomtemperature for 1 hour. Saturated NaHCO₃ (70 ml) was then added toquench the reaction. The aqueous layer was extracted with methylenechloride (3 times), the organic layers were combined and washed withbrine, then dried over Na₂ SO₄, filtered, and concentrated to about 50ml. The viscous solution was subjected to flash chromatography on Mercksilica gel in 30% methylene chloride in hexane. The desired fractionswere pooled and concentrated to give a clear oil, which solidified uponstanding overnight. The white solid was recrystallized from hexane toafford the vinyl dibromide title compound as hard, white crystals (5.010gm, 56%).

m.p. 52°-53° C. TLC: Rf 0.57 (5% EtOAc in hexane) Elemental Analysis forC₁₉ H₂₀ NBr₂ F: Calculated C, 51.73; H, 4.57; N, 3.18; Br, 36.22; F,4.31 Found C, 51.79; H, 4.52; N, 3.08; Br, 36.30; F, 4.21

G. (S)-4-[[[4-(4-Fluorophenyl)-2,6-bis(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

n-BuLi (2.5M in hexane, 6.54 ml, 16.36 mmol) was added dropwise to asolution of the dibromide from part F (2.000 gm, 4.54 mmol) in THF (20ml), stirring under argon at -78° C. The solution was allowed to stir 1hour at -78° C., then cannulated into a THF solution (20 ml) of thechloridate from Example 57, part G which had also been cooled to -78° C.The solution was stirred at-78° C. for 45 minutes, then quenched withsaturated NH₄ Cl. The solution was warmed to 0° C., and saturated NaHCO₃was added. The mixture was diluted with ether and the organic layer waswashed with brine, dried over Na₂ SO₄, filtered and concentrated to anorange oil. The oil was purified by flash. chromatography on Mercksilica gel in 40% EtOAc in hexane. Pure product fractions were combinedand evaporated to afford 0.660 gm of a yellow oil. Impure fractions werepooled, concentrated and purified again by flash chromatography in 35%EtOAc in hexane on Merck silica gel to afford an additional 0.360 gm ofthe title compound as a yellow oil (total yield, 1.020 gm, 33%).

TLC: Rf 0.64 (50% ETOAc in hexane) (For optimal results, the amount of2.5M n-BuLi should be 3.80 ml, 9.53 mmol.)

H.(S)-4-[[[4-(4-Fluorophenyl)-2,6-bis(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

(Bu)₄ NF (1.0M in THF, 4.47 ml, 4.47 mmol) was added to a solution ofthe silyl ether from part G (1.020 gm, 1.49 mmol) and acetic acid (0.45gm, 7.45 mmol) in THF (20 ml) under argon. The solution was allowed tostir 17 hours at room temperature, then diluted with EtOAc (to 50 ml)and washed with 5% KHSO₄ (3 times). The aqueous layers were extractedwith EtOAc (3 times). The organic layers were pooled and washed withbrine, then dried over Na₂ SO₄, filtered and concentrated to afford anorange oil. The oil was dissolved in ether and treated with excess CH₂N₂. Excess CH₂ N₂ was removed with a stream of argon, and the solutionwas concentrated to give a yellow oil. The oil was purified by flashchromatography on Merck silica gel in 35% acetone in hexane. The desiredfractions were pooled and concentrated to afford the title compound as ayellow oil (0.424 gm, 60%).

TLC: Rf 0.65 (50% acetone in hexane)

I.(S)-4-[[[4-(4-Fluorophenyl)-2,6-bis(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

NaOH (1M in water, 2.68 ml, 2.68 mmol) was added to a solution of thealcohol from part H (0.424 gm, 0.892 mmol) in dioxane (10 ml), which wasstirring under argon at room temperature. The solution was then heatedto 55° C. and allowed to stir 45 minutes. Additional NaOH (1M in water,2.0 ml, 2.0 mmol) was added to the solution. The solution was allowed tostir 3.5 hours at 55° C. After cooling to room temperature, the solutionwas concentrated to a white solid. The solid was then chromatographed onHP-20 resin, eluting first with water (200 ml) and then a lineargradient from 100% H₂ O (400 ml) to 100% MeOH (425 ml). The desiredfractions were pooled, the solvent removed on the rotovap, the residuetaken up in water and lyophilized to give Example 68 as a fluffy whitesolid (0.355 gm, 81%).

TLC: Rf 0.74 (6:3:1, n-propanol:NH₄ OH:H₂ O) Elemental Analysis for C₂₃H₂₅ NFPNa₂ O₅ * 1.40 H₂ O: Analysis: C, 53.47; H, 5.42; N, 2.71; F,3.63; P, 5.99 Found: C, 53.49; H, 5.11; N, 2.69; F, 3.51; P, 6.24

Example 69(S)-4-[[[6-Cyclohexyl-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A. 1-Cyclohexyl-3-(4-fluorophenyl)-2-propen-1-one

A sodium ethoxide solution (21% by weight in ethanol, 6.805 gm, 21 mmol)was added to a mixture of 1-cyclohexyl-1-ethanone (18.749 g, 140 mmol,from Aldrich) and 4-fluorobenzaldehyde (17.37 g, 140 mmol, from Aldrich)in ethanol (100 ml), stirring under argon. The solution was allowed tostir 1.5 hours. The reaction mixture was then concentrated to afford anorange oil. The oil was dissolved in ether, washed with saturated NH₄ Cland brine, then dried over Na₂ SO₄, filtered and concentrated to anorange oil. The oil was purified by distillation (bp=143° C. at 1.3 mmHg). The resultant yellowish oil slowly solidified to afford the titlecompound as hard yellow crystals (22.640 gm, 65%).

m.p. 44°-46° C. TLC: Rf 0.43 (5% EtOAc in hexane) Elemental Analysis forC₁₅ H₁₇ FO: Calculated: C, 77.56; H, 7.38; F, 8.18 Found: C, 77.57; H,7.58; F, 7.99

B.β-(4-Fluoro-2-phenyl)-α-(2-methyl-1-oxopropyl)-Δ-oxocyclohexanepentanoicacid, ethyl ester

A sodium ethoxide solution (21% by weight in ethanol, 0.530 gm, 7.79mmol) was added to a mixture of the enone from part A (12.930, 52 mmol)and ethyl isobutyrylacetate (12.32 gm, 77.9 mmol) in ethanol (200 ml).The solution was allowed to stir under argon at room temperature for 16hours. Additional ethanol (30 ml) was added to the flask to make aslurry of the partially solidified reaction mixture. A white solid wasthen filtered out of solution and recrystallized from hot hexane toafford the title compound as a waxy white solid (19.574 gm, 92%).

m.p. 75°-77° C. TLC: Rf 0.26 (10% EtOAc in hexane) Elemental Analysisfor C₂₃ H₃₁ FO₄ : Calculated: C, 70.74; H, 8.00; F, 4.87 Found: C,70.82; H, 8.21; F, 4.82

C.6-Cyclohexyl-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinecarboxylicacid, ethyl ester

NH₄ OAc (7.46 gm, 96.8 mmol) and Cu(OAc)₂ (14.49 gm, 72.6 mmol) wereadded to an acetic acid solution (100 ml) of the 1,5 diketone from partB (9.850 gm, 24.2 mmol). The solution was allowed to reflux 18 hoursunder argon. The solution was then poured into an ice-cold solution ofNH₄ OH/H₂ O (150 ml/200 ml). The mixture was extracted with ether(twice). The organic layers were combined and washed with water andbrine, then dried over Na₂ SO₄, and concentrated to afford a yellow oil.The oil was dissolved in hot hexane and cooled to afford the ester titlecompound as large yellowish crystals (4.300 gm, 48%).

m.p. 68°-70° C. TLC: Rf (10% EtOAc in hexane) Elemental Analysis for C₂₃H₂₇ NFO₂ : Calculated: C, 73.86; H, 7.44; N, 3.75; F, 5.08 Found: C,74.08; H, 7.52; N, 3.53; F, 5.00

D. 6-Cyclohexyl-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinemethanol

A THF solution (20 ml) of the ester from part C (4.000 gm, 10.8 mmol)was cooled to 0° C. and treated with LiAlH₄ (1.23 gm, 55.7 mmol). Thesolution was allowed to stir 20 minutes at 0° C., then warmed to roomtemperature and stirred for 2 hours. Additional LiAlH₄ (0.885 gm, 23mmol) was added to the solution at room temperature. The solutionstirred 20 minutes. The solution was then cooled to 0° C. and quenchedby dropwise addition of 2.1 ml of water, followed by 2.1 ml of 15% NaOH,and then 6.3 ml water. The aluminum paste was filtered out of solutionand the filtrate concentrated to afford a yellow oil. The oil wasdissolved in hot hexane and the resultant solution cooled to give thetitle compound as fine white needles (3.077 gm, 87%).

m.p. 101°-104° C. TLC: Rf 0.16 (5% EtOAc in hexane) Elemental Analysisfor C₂₁ H₂₅ NFO*0.27 H₂ O: Calculated: C, 76.15; H, 7.77; N, 4.23; F,5.74 Found: C, 76.43; H, 8.08; N, 3.95; F, 5.61

E.6-Cyclohexyl-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinecarboxaldehyde

DMSO (0.929 gm, 11.9 mmol) was added to a solution of oxalyl chloride(0.756 gm, 5.95 mmol) in methylene chloride (40 ml), which was cooled to-78° C. under argon. The solution was allowed to stir 10 minutes. Then,the alcohol from part D (1.50 gm, 4.58 mmol) was added to the flask as amethylene chloride (10 ml) solution. Gentle heating was required to getthe alcohol into solution. Triethylamine (3.65 ml) was added twentyminutes later. The solution was stirred for an additional 10 minutes,then was warmed to room temperature. The solution was diluted withether, washed with water and brine, then dried over Na₂ SO₄, filteredand concentrated to afford a yellow-brown oil. The compound was purifiedby flash chromatography on Merck silica gel in 5% EtOAc in hexane.Fractions containing pure product were combined and concentrated. Theresulting yellowish solid was recrystallized from hexane to give thetitle compound as hard, white crystals (1.239 gm, 83%).

m.p. 59°-61° C. TLC: Rf 0.33 (10% EtOAc in hexane) Elemental Analysisfor C₂₁ H₂₃ NFO*0.21 H₂ O: Calculated: C, 76.87; H, 7.19; N, 4.27; F,5.79 Found: C, 77.06; H, 7.56; N, 4.08; F, 5.78

F.3-(2,2-Dibromoethenyl)-6-Cyclohexyl-4-(4-fluorophenyl)-2-(1-methylethyl)pyridine

CBr₄ (1.55 gm, 4.60 mmol) was added as a methylene chloride solution (10ml) over 5 minutes to a mixture of triphenylphosphine (2.58, 9.85 mmol)and the aldehyde from part E (1.230 gm, 3.07 mmol) in methylene chloride(50 ml) that had been cooled to 0° C. The solution was stirred for anadditional 30 minutes. The reaction was quenched with saturated NaHCO₃and the solution allowed to warm to room temperature. The aqueous layerwas extracted with methylene chloride (twice) and the organic layerswere combined and washed with brine, then dried over Na₂ SO₄, filteredand concentrated to about 10 ml. The solution was subjected to flashchromatography on Merck silica gel in 30% methylene chloride in hexane.The desired fractions were pooled and concentrated to afford a clearoil, which solidified upon standing overnight. The white solid wasrecrystallized from hexane to afford the title compound as hard, whitecrystals (1.220 gm, 85%).

m.p. 98°-100° C. TLC: Rf 0.89 (5% EtOAc in hexane) Elemental Analysisfor C₂₀ H₁₆ NBr₂ FS: Calculated: C, 49.92; H, 3.35; N, 2.91; Br, 33.21;F, 3.95; S, 6.66 Found: C, 50.43; H, 3.25; N, 2.67; Br, 33.43; F, 3.95;S, 6.96

G.(S)-4-[[[6-Cyclohexyl-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

2.5M n-BuLi (1.68 ml, 4.2 mmol) was added dropwise to a solution of thedibromide from part F (3.976 gm, 2.10 mmol) in THF (15 ml) at -78° C.under argon. The solution was allowed to stir 1 hour at -78° C., thencannulated into a THF solution (15 ml) of the chloridate from Example57, part G which had also been cooled to -78° C. The resultant red-ambersolution was stirred for 45 minutes, then quenched with saturated NH₄ Cl(15 ml) and warmed to 0° C. Then, saturated NaHCO₃ was added to thesolution, which was subsequently warmed to room temperature. The mixturewas diluted with ether and the organic layer was washed with brine,dried over Na₂ SO₄, filtered and concentrated to give an orange oil. Theoil was purified by flash chromatography on Merck silica gel in 40%EtOAc in hexane. The desired fractions were combined and evaporated toafford the title compound as a beige foam (1.018 gm, 68%).

TLC: Rf 0.35 (40% EtOAc in hexane)

H.(S)-4-[[[6-Cyclohexyl-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxy]butanoicacid, methyl ester

(Bu)₄ NF (1.0M in THF, 4.26 ml, 4.26 mmol) was added to a mixture ofsilyl ether from part G (1.018 gm, 1.42 mmol) and acetic acid (0.42 gm,7.20 mmol) in THF (10 ml). The solution was allowed to stir 18 hours atroom temperature under argon. The solution was diluted with EtOAc (20ml) and then washed with 5% KHSO₄ (3×20 ml). The aqueous layers wereback-extracted with EtOAc (3 times). The organic layers were pooled andwashed with brine, then dried over Na₂ SO₄, filtered and concentrated toafford a brown oil. The oil was dissolved in ether (15 ml) and treatedwith excess CH₂ N₂. Excess CH₂ N₂ was removed with a stream of argon,and the solution was concentrated to a brown oil. The oil was purifiedby flash chromatography on Merck silica gel in 35% acetone in hexane.The desired fractions were pooled and concentrated to afford the titlecompound as a beige foam (0.370 gm, 51%).

TLC: Rf 0.49 (40% acetone in hexane)

I.(S)-4-[[[6-Cyclohexyl-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

NaOH (1M in water, 2.10 ml, 2.10 mmol) was added to a solution of thepart H compound (0.370 gm, 0.72 mmol) in dioxane (10 ml). The solutionwas then heated to 55° C., allowed to stir 45 minutes and thenconcentrated to a white solid. The residue was dissolved in water andchromatographed on HP-20 resin, eluting first with water (200 ml), thenwith 50% MeOH in water (400 ml), then with MeOH (200 mol). The desiredfractions were pooled and concentrated. The residue was taken up inwater and lyophilized to give Example 69 as a fluffy white solid (0.374gm, 98%).

TLC: Rf 0.67 (6:3:1, n-propanol:NH₄ OH:H₂ O) Elemental Analysis for C₂₆H₂₉ NFNa₂ PO₅ *1.60 H₂ O: Calculated: C, 55.74; H, 5.79; N, 2.50; F,3.39; P, 5.53 Found: C, 55.74; H, 5.64; N, 2.66; F, 3.22; P 5.63

Example 70(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-thienyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A. 3-(4-Fluorophenyl)-1-(2-thienyl)-2-propen-1-one

A solution of sodium ethoxide (21% by weight in EtOH, 0.68 gm, 10 mmol)was added to a solution of 2-acetylthiophene (12.60 gm, 100 mmol, fromAldrich) and 4-fluorobenzaldehyde (12.41 gm, 100 mmol, from Aldrich) inEtOH (50 ml) and the mixture stirred under argon for 15 minutes. MoreEtOH (25 ml) was then added to make a slurry of the reaction mixture,which had partially solidified. Acetic acid (0.60 gm, 11 mmol) was addedand a yellow solid filtered out of solution. The solid wasrecrystallized from EtOAc and hexane to afford the title compound aslong, pale yellow needles (17.679 gm, 71%).

m.p. 117°-120° C. TLC: Rf 0.24 (10% EtOAc in hexane) Elemental Analysisfor C₁₃ H₉ FSO*0.21 H₂ O: Calculated: C, 66.13; H, 4.02; F, 8.05; S,13.58 Found: C, 66.14; H, 3.95; F, 8.05; S, 13.58

B.β-(4-Fluoro-2-phenyl)-α-(2-methyl-1-oxopropyl)-Δ-oxo-2-thiophenepentanoicacid, ethyl ester

A solution of sodium ethoxide (21% by weight in EtOH, 0.530 gm, 7.79mmol) was added to a solution of ethyl isobutyrylacetate (16.1 gm, 101mmol) and the enone from part A (16.975 gm, 67.9 mmol) in EtOH (300 ml)and the mixture stirred under argon at room temperature for 17 hours.Acetic acid (0.667 gm, 11 mmol) was added to quench the reaction, andthe solution was concentrated. The oily, yellow solid was dissolved inEtOAc and washed with saturated NH₄ Cl, H₂ O, and brine, then dried overMgSO₄, filtered and concentrated to give an oily, yellow solid. Thesolid was recrystallized from hexane to afford the title compound asfine white needles (21.413 gm, 77%).

m.p. 92°-105° C. TLC: Rf 0.25 & 0.30 (20% EtOAc in hexane) ElementalAnalysis for C₂₁ H₂₃ FSO₄ : Calculated: C, 64.59; H, 5.94; F, 4.87; S,8.21 Found: C, 64.68; H, 5.98; F, 5.03; S, 8.27

C.4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-thienyl)-3-pyridinecarboxylicacid, ethyl ester

NH₄ OAc (8.176 gm, 106 mmol) and Cu(OAc)₂ (15.57 gm, 78 mmol) were addedto an acetic acid solution (150 ml) of the 1,5 diketone from part B(10.025 gm, 26.5 mmol) and the mixture was allowed to reflux 18 hoursunder argon. The solution was then poured into an ice-cold solution ofNH₄ OH/H₂ O (200 ml/250 ml). The mixture was extracted with ether andEtOAc, washed with water and saturated NaCl, then dried over Na₂ SO₄,and concentrated to afford a yellow-brown oil. Flash chromatography wasperformed on the oil in 5% EtOAc in hexane on Merck silica gel. Productfractions were pooled and concentrated to a yellow solid. The solid wasrecrystallized from hexane to afford the title compound as hard yellowcrystals (5.627 gm, 58%).

m.p. 114°-115° C. TLC: Rf 0.78 (20% EtOAc in hexane)

D. 4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-thienyl)-3-pyridinemethanol

A THF solution (20 ml) of the ester from part C (5.620 gm, 15.2 mmol)was cooled to 0° C. and treated with LiAlH₄ (1.730 gm, 72 mmol). Thesolution was allowed to stir twenty minutes at 0° C. and then was warmedto room temperature. Additional LiAlH₄ (1.000 gm, 26.3 mmol) was addedto the solution. The solution was allowed to stir 30 minutes, thencooled to 0° C. and quenched by dropwise addition of 2.73 ml of waterfollowed by 2.73 ml of 15% NaOH, then 8.20 ml of water. The aluminumpaste was filtered out of solution and the filtrate was concentrated toa yellow solid. The solid was recrystallized from hexane to afford thetitle compound as hard yellow crystals (4.067 gm, 82%).

m.p. 151°-153° C. TLC: Rf 0.42 (20% EtOAc in hexane) Elemental Analysisfor C₁₉ H₁₈ NFSO*0.06 H₂ O: Calculated: C, 69.47; H, 5.56; N, 4.26; F,5.78; S, 9.76 Found: C, 69.77; H, 5.50; N, 3.96; F, 5.67; S, 9.63

E.4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-thienyl)-3-pyridinecarboxaldehyde

DMSO (1.53 gm, 19.6 mmol) was added to a solution of oxalyl chloride(1.25 gm, 9.80 mmol) in methylene chloride (40 ml), which had beencooled to -78° C. under argon. The solution was allowed to stir 10minutes, then the alcohol from part D (2.456 gm, 7.55 mmol) was added tothe flask as a methylene chloride (20 ml) solution. Triethylamine (5.25ml, 38 mmol) was added 20 minutes later and the solution stirred for anadditional 10 minutes, then warmed to room temperature. The solution wasdiluted with ether and washed with water and brine, then dried over Na₂SO₄, filtered and concentrated to afford a yellow solid. The solid wasrecrystallized from hexane to afford the title compound as hard, yellowcrystals (2.255 gm, 93%).

m.p. 123°-125° C. TLC: Rf 0.50 (20% EtOAc in hexane)

F.3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-6-(2-thienyl)pyridine

A solution of CBr₄ (3.36 gm, 10 mmol) in methylene chloride (15 ml) wasadded over 15 minutes to a solution of triphenylphosphine (5.59 gm, 21.3mmol) and the aldehyde from part E (2.155 gm, 6.67 mmol) in methylenechloride (60 ml), which was stirring under argon at 0° C. The solutionstirred for an additional 20 minutes at 0° C., then was warmed to roomtemperature and stirred 45 minutes. Saturated NaHCO₃ (15 ml) was addedto quench the reaction. The aqueous layer was extracted with methylenechloride (twice), the organic layers were combined and washed withbrine, then dried over Na₂ SO₄, filtered and concentrated to about 15ml. The viscous solution was purified by flash chromatography on Mercksilica gel in 40% methylene chloride in hexane. Pure fractions werepooled and concentrated to afford a white foam. The foam was dissolvedin hexane, and the solution cooled to afford the title compound as paleyellow crystals (2.942 gm, 92%)

m.p. 107°-108° C. TLC: Rf 0.70 (10% EtOAc in hexane) Elemental Analysisfor C₂₀ H₁₆ NBr₂ FS: Calculated: C, 49.92; H, 2.91; N, 2.91; Br, 33.21;F, 3.95; S, 6.66 Found: C, 50.43; H, 3.25; N, 2.67; Br, 33.43; F, 3.95;S, 6.96

G.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-thienyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

n-BuLi (2.5M in hexane, 3.34 ml, 8.34 mmol) was added dropwise to asolution of the dibromide from part F (2.000 gm, 4.17 mmol) in THF (20ml) at -78° C. under argon. The solution was allowed to stir 1 hour at-78° C., then cannulated into a THF solution (15 ml) of thephosphonochloridate from Example 57, part G, which had also been cooledto -78° C. The resultant red-amber solution was stirred for 45 minutes,then quenched with saturated NH₄ Cl, warmed to 0° C. and then saturatedNaHCO₃ was added to the solution. The mixture was diluted with ether,the organic layer was washed with brine, then dried over Na2SO₄,filtered and concentrated to give an orange oil. The oil was purified byflash chromatography on Merck silica gel in 40% EtOAc in hexane. Pureproduct fractions were combined and concentrated to afford the titlecompound as a beige foam (1.018 gm, 68%).

TLC: Rf 0.35 (40% EtOAc in hexane)

H.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-thienyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

A solution of (Bu)₄ NF (1M in THF, 6.8 ml, 6.8 mmol) was added to asolution of the silyl ether from part G (1.640 gm, 2.2 mmol) and aceticacid (0.66 gm, 11.0 mmol) in THF (15 ml) and the solution allowed tostir at room temperature 16 hours. The solution was diluted with EtOAc,then washed with 5% KHSO₄ (3 times). The aqueous layers were extractedwith EtOAc (3 times). The organic layers were pooled and washed withbrine, then dried over Na₂ SO₄, filtered and concentrated to afford ayellow oil. The oil was dissolved in ether and treated with excess CH₂N₂. Excess CH₂ N₂ was removed with a stream of argon, and the solutionwas concentrated to give a yellow oil. The oil was purified by flashchromatography on Merck silica gel in 35% acetone in hexane. Pureproduct fractions were pooled and concentrated to afford the titlecompound as a beige foam (0.870 gm, 75%).

TLC: Rf 0.63 (50% acetone in hexane)

I.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-thienyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A solution of the part H compound (0.870 gm, 1.66 mmol) in dioxane (10ml) was treated with a solution of NaOH (1M in water, 4.95 ml, 4.95mmol). The solution was then heated to 55° C. and allowed to stir 1.5hours. The mixture was concentrated to a white solid. The residue waschromatographed on HP-20 resin, eluting first with water (200 ml), thenwith 50% MeOH in water (400 ml), then with MeOH (200 ml). The desiredfractions were pooled and concentrated, the residue taken up in waterand lyophilized to give Example 70 as a fluffy white solid (0.807 gm,92%).

TLC: Rf 0.70 (6:3:1, n-propanol:NH₄ OH:H₂ O) Elemental Analysis for C₂₄H₂₁ NFNa₂ PSO₅ *1.55 H₂ O: Calculated: C, 51.53; H, 4.34; N, 2.50; F,3.40; P, 5.54 Found: C, 51.58; H, 4.25; N, 2.58; F, 3.72; P, 5.71

Example 71(S)-4-[[[6-Cyclopropyl-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A. 1-Cyclopropyl-3-(4-fluorophenyl)-2-propen-1-one

A mixture of 4-fluorobenzaldehyde (9.30 g, 75.00 mmol, Aldrich) andcyclopropyl methyl ketone (6.30 g, 75.00 mmol) in absolute ethanol (100ml) was treated with a solution of sodium ethoxide in ethanol (21% byweight solution; 2.79 ml, 7.50 mmol). After stirring for 2 hours at roomtemperature, additional 4-fluorobenzaldehyde was added (1.86 g, 15.00mmol). The reaction mixture was stirred for 2 hours, concentrated to 1/3volume and partitioned between 50% saturated NH₄ Cl/EtOAc (100 ml/250ml). The layers were separated and the aqueous portion was extractedwith EtOAc (twice) and the combined organics were washed with H₂ O(twice) and brine, dried (Na₂ SO₄) and concentrated. The yellow oilyresidue was distilled (Vigroux column, bp 115°-120° C., 0.6 mm Hg) toafford the title compound as a colorless oil (12.8 g, 89.7%).

R_(f) 0.37 (15% EtOAc/hexane), UV

B. β-(4-Fluorophenyl)-α-(2-methyl-1-oxopropyl)-Δ-oxocyclopropylpentanoicacid, ethyl ester

A mixture of the compound from part A (6.65 g, 35.00 mmol) and ethylisobutyrylacetate (8.47 ml, 52.50 mmol) in absolute ethanol (50 ml) wastreated with a solution of sodium ethoxide in ethanol (21% by weightsolution, 6.51 ml, 17.00 mmol). The reaction mixture was stirred at roomtemperature for 48 hours, then concentrated to 1/3 volume andpartitioned between 50% saturated NH₄ Cl/EtOAc (100 ml/250 ml). Thelayers were separated and the aqueous portion was extracted with EtOAc(twice) and the combined organics were washed with H₂ O (twice) andbrine, then dried (Na₂ SO₄) and concentrated. The dark oily residue waspurified by flash chromatography (Merck silica gel, 5% EtOAc/hexane) toafford the title compound as a colorless oil (9.0 g, 74.3%, mixture ofdiastereomers).

R_(f) 0.29+0.31 (25% EtOAc/hexane), UV

C.6-(Cyclopropyl-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinecarboxylicacid, ethyl ester

A mixture of the part B compound (9.00 g, 25.7 mmol), ammonium acetate(5.94 g, 77.10 mmol) and copper (II) acetate (12.82 g, 64.25 mmol) inglacial acetic acid (80 ml) was heated at 115° C. for 16 hours (TLCafter 30 minutes indicated the presence of two products and almost nostarting material). The reaction mixture was cooled and carefully pouredinto an ice cold mixture of concentrated NH₄ OH (100 ml) and H₂ O (200ml). The mixture was extracted with ether (twice) and the ether extractswere washed with H₂ O (twice) and brine, then dried (MgSO₄), filteredand concentrated. The dark oily residue was purified by flashchromatography (10% EtOAc/hexane) to afford Compound III as a colorlessoil (3.45 g, 41.0%).

R_(f) 0.62 (20% EtOAc/hexane), UV

D.6-(Cyclopropyl-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinemethanol

A cold (0° C.) solution of the ester from part C (3.40 g, 11.03 mmol) indry THF (50 ml) was treated with LiAlH₄ (1.25 g, 33.00 mmol). Tenminutes after the addition the cooling bath was removed and the reactionmixture stirred at room temperature for 3 hours and then refluxed for 24hours. The reaction mixture was cooled to 0° C. and carefully quenchedin succession with 1.25 ml of H₂ O in THF (10 ml), then 1.25 ml 15% NaOHand finally 3.0 ml H₂ O. The precipitated aluminum salts were filteredand washed with EtOAc and ether. The filtrate was washed with H₂ O andbrine, dried (Na₂ SO₄), filtered and concentrated under reduced pressureto give an oily residue. Purification by flash chromatography (Mercksilica gel, 5% EtOAc/hexane) yielded the title compound as a colorlessoil which solidified on standing under high vacuum. Recrystallizationfrom hot hexane afforded the title compound as a white solid (2.32 g,79.3%).

m.p. 94°-95° C. R_(f) 0.36 (20% EtOAc/hexane), UV Analysis for C₁₈ H₂₀NFO: Calc'd: C, 75.76; H, 7.06; N, 4.91; F, 6,66 Found: C, 75.23; H,7.13; N, 4.92; F, 6.71

E.6-(Cyclopropyl-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinecarboxaldehyde

A -78° C. solution of oxalyl chloride (0.85 ml, 9.67 mmol) in CH₂ Cl₂(70 ml) was treated dropwise with a solution of dry DMSO (1.37 ml, 19.34mmol) in CH₂ Cl₂ (10 ml). After 15 minutes, a solution of the alcoholfrom part D (2.30 g, 8.06 mmol) in CH₂ Cl₂ (10 ml) was added dropwise tothe above solution. After 20 minutes, triethylamine (6.75 ml, 48.36mmol) was added and the mixture was stirred at -78° C. for 20 minutesand then warmed to room temperature. After 1 hour, the reaction wasquenched with H₂ O and diluted with ether. The layers were separated andaqueous layer was extracted with ether (twice). The combined organicsolutions were washed with H₂ O (twice) and brine, then dried (MgSO₄),filtered and concentrated under reduced pressure. The oily residue waspurified by flash chromatography (Merck silica gel, 10% EtOAc/hexane),affording the aldehyde title compound as a colorless oil, whichsolidified on standing under high vacuum (1.74 g, 76.3%).

m.p. 67°-68° C. R_(f) 0.56 (20% EtOAc/hexane), UV Analysis for C₁₈ H₁₈NFO: Calc'd: C, 76.30; H, 6.40; N, 4.94; F, 6.71 Found: C, 75.99; H,6.43; N, 4.69; F, 6.66

F.6-Cyclopropyl-3-(2,2-dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)pyridine

A solution of carbon tetrabromide (2.89 g, 8.73 mmol) in CH₂ Cl₂ (10 ml)was added dropwise over a 5-minute period to a cold (0° C.) solution ofthe aldehyde from part E (1.65 g, 5.82 mmol) and triphenylphosphine(4.58 g, 17.46 mmol) in CH₂ Cl₂ (60 ml). The mixture was stirred at 0°C. for 10 minutes and then at room temperature for 1 hour. The solutionwas quenched with saturated NaHCO₃ and extracted twice with CH₂ Cl₂. Thecombined organic layers were dried (Na₂ SO₄), filtered, concentrated to1/3 volume and applied on Merck silica gel column (50% CH₂ Cl₂ /hexane).Flash chromatography afforded the title compound as a colorless oil(2.36 g, 93.0%).

R_(f) 0.58 (10% EtOAc/hexane), UV

G.(S)-4-[[[6-Cyclopropyl-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

A solution of the dibromide from part F (2.00 g, 4.56 mmol) in THF (15ml) at -78° C. was treated with n-BuLi (2.5M in hexane, 3.82 ml, 9.57mmol) over a 1-minute period. The brown-red reaction mixture was stirredfor 30 minutes at -78° C. and then transferred via cannula to -78° C.solution of the phosphonochloridate from Example 57, part G in THF (15ml). The dark-brown reaction mixture was stirred -78° C. for 45 minutesand then quenched with 50% saturated NH₄ Cl. After warming to roomtemperature, the solution was diluted with H₂ O and poured intosaturated NaHCO₃. The layers were separated and the aqueous layer wasextracted once with ether. The combined organic layers were washed withbrine, dried (Na₂ SO₄), filtered and concentrated under reducedpressure. The dark oily residue was purified by flash chromatography(Merck silica gel, 20% EtOAc/hexane) to afford Compound G as a paleyellow oil (2.11 g, 65.0%).

R_(f) 0.18 (30% EtOAc/hexane), UV

H.(S)-4-[[[6-Cyclopropyl-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

To a solution of the acetylinic phosphonate from part G (2.10 g, 2.95mmol) in THF (15 ml) was added HOAc (0.67 ml, 11.8 mmol), followed bytetra-n-butylammonium fluoride (1.0M in THF, 8.85 ml, 8.85 mmol). Thereaction mixture was stirred at room temperature under argon for 24hours. The solution was diluted with EtOAc and washed three times with5% KHSO₄. The aqueous layer was back-extracted twice with EtOAc and thecombined organic extracts were dried (Na₂ SO₄), filtered andconcentrated under reduced pressure. The dark oil was dissolved in ether(added a few drops of THF to obtain a clear solution), cooled to 0° C.and treated with excess diazomethane in ether for 20 minutes. The excessdiazomethane was destroyed by the addition of HOAc. Solvent removal gavea dark oily residue, which was purified by flash chromatography (Mercksilica gel, 30% acetone/hexane). The product was obtained as a colorlessoil (0.77 g, 55.7%).

R_(f) 0.30 (40% acetone/hexane) UV

I.(S)-4-[[[6-Cyclopropyl-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

The diester from part H (0.76 g, 1.60 mmol) in dioxane (15 ml) wastreated with 1N NaOH (5.60 ml, 5.60 mmol) at room temperature and thenheated at 50° C. for 2.5 hours. The reaction mixture was concentratedand the residue was chromatographed on HP-20 resin, eluting first withH₂ O (300 ml), followed by 25% MeOH/H₂ O (300 ml), 50% MeOH/H₂ O (300ml) and finally MeOH (100ml). The collected product fractions wereevaporated, dissolved in H₂ O, filtered, frozen and lyophilized to giveExample 71 as a white lyophilate (0.61 g, 78.2%).

R_(f) 0.27 (8:1:1--CH₂ Cl₂ :CH₃ OH:HOAc), UV Analysis for C₂₃ H₂₃ NFPO₅Na₂ ×2.67 H₂ O: Calc'd: C, 51.40; H, 5.31; N, 2.61; F, 3.54; P, 5.76Found: C, 51.70; H, 5.13; N, 2.31; F, 3.39; P, 5.55

Example 72(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2,3,5,6-tetrafluorophenyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A. 3-(4-Fluorophenyl)-1-(pentafluorophenyl)-2-propen-1-one

A solution of sodium ethoxide (21% in EtOH, 0.32 gm, 4.76 mmol) wasadded to a mixture of 1-(pentafluorophenyl)-1-ethanone (5.91 gm, 47.6mmol, Aldrich) and 4-fluorobenzaldehyde (10.00 gm, 47.6 mmol) stirringin ethanol (100 ml) under argon. The solution was allowed to stir atroom temperature for 18 hours, then EtOH was evaporated to afford ayellowish, oily solid. The solid was redissolved in ether, washed withwater and brine, then dried over MgSO₄, filtered and concentrated togive a yellow residue. The residue was purified by flash chromatographyon Merck silica gel in 5% EtOAc/hexane. Fractions containing the productwere combined and concentrated to a yellow solid. The solid wasrecrystallized from hexane to afford the title compound as large yellowcrystals (8.220 gm, 52%).

m.p. 80°-84° C. TLC: Rf 0.69 (10% EtOAc in hexane) Elemental Analysisfor C₁₅ H₆ F₆ O: Calc'd: C 56.98 H 1.91 F 36.05 Found: C 56.81 H 1.73 F35.43

B.2,3,4,5,6-Pentafluoro-β-(4-fluorophenyl)-α-(2-methyl-1-oxopropyl)-Δ-oxobenzenepropanoicacid, ethyl ester

A solution of sodium ethoxide (21% by weight in EtOH, 0.530 gm, 7.79mmol) was added to an EtOH solution (100 ml) of the enone from part A(7.220 gm, 21.6 mmol) and ethyl isobutyrylacetate (5.12 gm, 32.4 mmol)stirring under argon at room temperature. In less than 5 minutes, thereaction mixture partially solidified. Ethanol (75 ml) was added to theflask to make a slurry of the reaction mixture. Acetic acid (0.214 gm,3.56 mmol) was then added to quench the reaction and a yellowish solidwas filtered out of solution. The solid was recrystallized fromEtOAc/hexane to afford the title compound as hard yellow crystals (8.737gm, 98%).

m.p. 84° C. TLC: Rf 0.30 (15% EtOAc in hexane)

C.4-(4-Fluorophenyl)-2-(1-methylethyl)-6-pentafluorophenyl-3-pyridinecarboxylicacid, ethyl ester

NH₄ OAc (3.20 gm, 41.78 mmol) and Cu(OAc)₂ (6.89 gm, 34.75 mmol) wereadded to an acetic acid solution (20 ml) of the 1,5 diketone from part B(6.600 gm, 13.9 mmol). The mixture was allowed to reflux 18 hours underargon, then cooled and poured into an ice-cold solution of NH₄ OH/H₂ O(50 ml/75 ml). The mixture was extracted with ether and EtOAc, theorganic layers were combined and washed with water and saturated NaCl,then dried over Na₂ SO₄ and concentrated to afford an amber oil. Flashchromatography was performed on the oil in 5% EtOAc in hexane on Mercksilica gel. Product fractions were pooled and concentrated to afford thetitle compound as a clear oil (4.890 gm, 78%).

TLC: Rf 0.75 (15% EtOAc in hexane)

D.4-(4-Fluorophenyl)-2-(1-methylethyl)-6-2,3,5,6-tetrafluorophenyl-3-pyridinemethanol

A THF solution (20 ml) of the ester from part C (1.425 gm, 3.14 mmol)was cooled to 0° C. and treated with LiAlH₄ (0.358 gm, 9.4 mmol). Thesolution was allowed to stir 20 minutes at 0° C., then was warmed toroom temperature and stirred for an additional 3 hours. The solution wasthen cooled to 0° C. and quenched by dropwise addition of 1.1 ml ofwater, followed by 1.1 ml of 15% NaOH, and then 3.3 ml water. Thealuminum paste was filtered out of solution. The filtrate wasconcentrated to a yellow solid. The solid was recrystallized from hexaneto afford the title compound as hard yellow crystals (1.014 gm, 80%).

m.p. 130°-132° C. Rf 0.26 (15% EtOAc in hexane)

E.4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2,3,5,6-tetrafluorophenyl)-3-pyridinecarboxaldehyde

DMSO (0.79 gm, 10.12 mmol) was added to a -78° C. solution of oxalylchloride (0.64 gm, 5.06 mmol) in methylene chloride (40 ml). After thesolution stirred 20 minutes, the part D compound (1.595 gm, 3.89 mmol)was added dropwise to the flask as a methylene chloride (40 ml)solution, and the solution stirred for 20 minutes. Triethylamine (2.71ml) was added to the solution, which was stirred an additional 10minutes cold and then at room temperature for 45 minutes. The solutionwas diluted with ether, washed with water (twice) and brine, then driedover Na₂ SO₄, filtered and concentrated to afford a yellow solid. Thesolid was purified by flash chromatography on Merck silica gel in 5%EtOAc in hexane. Fractions containing the product were pooled andconcentrated to a yellow solid. The solid was recrystallized fromEtOAc/hexane to afford the title compound as yellowish crystals (1.25gm, 80%).

TLC: Rf 0.39 (15% EtOAc in hexane)

F.3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-6-(2,3,5,6-tetrafluorophenyl)pyridine

A CH₂ Cl₂ solution (40 ml) of CBr₄ was added over 10 minutes to a 0° C.solution of triphenylphosphine (2.55 gm, 9.72 mmol) and the aldehydefrom part E (1.24 gm, 3.04 mmol) in methylene chloride (40 ml). Thesolution stirred for 45 minutes, then was warmed to room temperatureover 30 minutes and the reaction quenched with saturated NaHCO₃ (15 ml).The aqueous layer was back-extracted with methylene chloride (twice),the organic layers combined and washed with brine, then dried over Na₂SO₄, filtered concentrated to about 10 ml. The solution was purified byflash chromatography on Merck silica gel in 40% methylene chloride inhexane. The desired fractions were pooled and concentrated to a whitesolid. The solid was recrystallized from hot hexane to afford the titlecompound as hard white crystals (1.346 gm, 77%).

m.p. 77° C. TLC: Rf 0.73 (15% EtOAc in hexane)

G.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2,3,5,6-tetrafluorophenyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]acid,methyl ester

2.5M n-BuLi (1.92 ml, 4.8 mmol) was added dropwise to a -78° C. solutionof the dibromide from part F (1.346 gm, 2.40 mmol) in THF (20 ml). Thesolution was allowed to stir 1 hour at -78° C. and then cannulated intoa -78° C. THF solution (15 ml) of the phosphonochloridate from Example57, part G. The resultant red-amber solution was stirred for 45 minutes,then was quenched with saturated NH₄ Cl (15 ml) and warmed to 0° C.Then, saturated NaHCO₃ was added to the solution. The aqueous layer wasback-extracted with ether, the organic layers combined and washed withbrine (1×50 ml), then dried over Na₂ SO₄, filtered and concentrated togive an orange oil. The oil was purified by flash chromatography onMerck silica gel in 40% EtOAc in hexane. Pure product fractions werecombined and evaporated to afford the title compound as a beige foam(0.584 gm, 50%).

TLC: Rf 0.35 (40% EtOAc in hexane)

H.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2,3,5,6-tetrafluorophenyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

To solution of (Bu)₄ NF (1.0M in THF, 3.57 ml, 3.57 mmol) was added aTHF solution (15 ml) of the silyl ether from part G (0.584 gm, 0.696mmol) and acetic acid. The solution was allowed to stir 16 hours at roomtemperature. The solution was diluted with EtOAc and washed with 5%KHSO₄ (three times). The aqueous layers were back-extracted with EtOAc(three times). The organic layers were pooled and washed with brine,then dried over Na₂ SO₄, filtered and concentrated to afford a yellowoil. The oil was dissolved in ether (15 ml) and treated with excess CH₂N₂. Excess CH₂ N₂ was removed with a stream of argon, and the solutionwas concentrated to a yellow oil. The oil was purified by flashchromatography on Merck silica gel in 40% acetone in hexane. The desiredfractions were pooled and concentrated to afford the title compound as abeige foam (0.305 gm, 73%).

TLC: Rf 0.56 (50% acetone in hexane)

I.(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2,3,5,6-tetrafluorophenyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A solution of NaOH (1.0M in water, 1.53 ml, 1.53 mmol) was added to adioxane solution (5 ml) of the part H compound (0.305 gm, 0.51 mmol).The solution was heated to 55° C. and allowed to stir 2 hours.Additional NaOH (1M in water, 1.0 ml, 1.0 mmol) was added to thesolution which was allowed to stir another hour. The mixture was cooledto room temperature and concentrated to a white solid. The residue waschromatographed on HP-20 resin, eluting first with water (200 ml), thenwith 50% MeOH in water (400 ml), and finally with MeOH (200 ml). Thedesired fractions were pooled and concentrated, the residue taken up inwater and lyophilized to give Example 72 as a fluffy white solid (0.807gm, 92%).

TLC: Rf 0.59 (6:3:1, n-propanol:NH₄ OH:H₂ O) Elemental Analysis for C₂₆H₁₆ NF₅ Na₂ PO₅ * 4.60 H₂ O: Calc'd: C 45.90 H 4.18 N 2.06 F 13.96 P4.55 Found: C 45.66 H 3.68 N 2.16 F 13.66 P 4.43

Example 73(S,E)-4-[[2-[6-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A.6-(1,1-Dimethylethyl)-3-(1-ethynyl)-4-(4-fluorophenyl)-2-(1-methylethyl)pyridine

To a solution of compound F from Example 61 (4.5 g, 9.88 mmol) in THF(20 ml) at -78° C. was added n-BuLi (2.5M in hexanes, 9.88 ml, 24.7mmol). The resulting blue-green reaction mixture was stirred for 1.5hours at -78° C. The mixture was quenched with saturated NH₄ Cl, warmedto room temperature, diluted with ether and the layers were separated.The aqueous layer was extracted with ether (2×50 ml) and the combinedorganic layers were washed with brine, dried (MgSO₄), and concentrated.The yellow oily residue was purified by flash chromatography (Mercksilica gel, 2.5% EtOAc/hexane) affording compound A as a colorless oil(2.75 g, 94.5%).

R_(f) 0.62 (10% EtOAc/hexane), UV

B.6-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-3-(2-iodoethenyl)-2-(1-methylethyl)-pyridine

A mixture of the compound prepared in part A (2.57 g, 8.70 mmol),tributyltin hydride (4.68 ml, 17.40 mmol) and α,α-azoisobutyronitrile(18.5 mg) was heated at 140° C. in an oil bath. After 1.5 hours, anadditional 34.6 mg of α,α-azoisobutyronitrile was added and heatingcontinued for additional 1.5 hours. The reaction mixture was cooled toroom temperature, diluted with ether (100 ml) and treated with 12 (4.5g). After stirring for 3 hours, the reaction mixture was washed with 10%Na₂ S₂ O₃ ×5 H₂ O (3×50 ml), 10% NH₄ OH (2×25 ml) and brine, then dried(MgSO₄) and concentrated. The yellow oily residue was purified by flashchromatography (Merck silica gel, 2% EtOAc/hexane), affording theproduct as a white solid. Recrystallization from hexane affordedcompound B as white crystals (2.77 g, 83.7%).

m.p. 78.0°-80.0° C. Analysis for C₂₀ H₂₃ NFI: Calc'd: C, 56.75; H, 5.48;N, 3.31; F, 4.49 Found: C, 57.23; H, 5.34; N, 3.28; F, 4.43

C.(S,E)-4-[[2-[6-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethenyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

A solution of the part B vinyl iodide (2.77 g, 6.54 mmol) in THF (15 ml)was added to a -78° C. solution of t-BuLi (1.7M in hexanes, 8.08 ml,13.74 mmol) in THF (20 ml) over a 4-minute period. The dark blue-greenreaction mixture was stirred for 1.5 hours at -78° C., then cooled to-100° C. and and transferred via cannula to -100° C. solution of thephosphonochloridate from Example 57, part G in THF (20 ml). Theyellow-orange reaction mixture was stirred at -100° C. for 45 minutesand then quenched with 50% saturated NH₄ Cl. After warming to roomtemperature, the solution was diluted with H₂ O and poured intosaturated NaHCO₃. The layers were separated and the aqueous layer wasextracted once with ether. The combined organic layers were washed withbrine, dried (Na₂ SO₄), filtered and concentrated under reducedpressure. The dark oily residue was purified by flash chromatography(Merck silica gel, 40% EtOAc/hexane) to afford the title compound as abeige foam (2.20 g, 46.0%).

R_(f) 0.23 (40 % EtOAc/hexane), UV

D.(S,E)-4-[[2-[6-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethenyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

To a solution of the part C silyl ether (2.20 g, 3.00 mmol) in THF (15ml) was added HOAc (0.68 ml, 9.00 mmol), followed bytetra-n-butylammonium fluoride (1.0M in THF, 9.00 ml, 9.00 mmol). Thereaction mixture was stirred at room temperature under argon for 20hours. The solution was diluted with ether (100 ml) and washed twicewith saturated NaHCO₃ and brine, then dried (MgSO₄) and concentratedunder reduced pressure. The oily residue was purified by flashchromatography (Merck silica gel, 25% acetone/hexane). Compound D wasobtained as as a colorless oil (1.05 g, 67.0%).

R_(f) 0.18 (40% acetone/hexane) UV

E.(S,E)-4-[[2-[6-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

The part D diester (0.20 g, 0.40 mmol) in dioxane (15 ml) was treatedwith 1N NaOH (1.40 ml, 1.40 mmol) at room temperature and then heated at50° C. for 2 hours. The solvent was evaporated and the residue waschromatographed on HP-20 resin, eluting first with H₂ O (300 ml),followed by 25% MeOH/H₂ O (300 ml), 50% MeOH/H₂ O (300 ml) and finallyMeOH (100 ml). The collected product fractions were evaporated,dissolved in H₂ O, filtered, frozen and lyophilized to give Example 73as a white lyophilate (0.128 g, 63.3%).

R_(f) 50 (8:1:1--CH₂ Cl₂ :CH₃ OH:HOAc), UV Analysis for C₂₄ H₂₉ NFPO₅Na₂ ×2.1 H₂ O: Calc'd: C, 52.87; H, 6,14; N, 2.57; F, 3.48; P, 5.68Found: C, 52.94; H, 6.24; N, 2.50; F, 3.36; P, 5.63

Example 74(S)-4-[[2-[6-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A.(S)-4-[[2-[6-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

The solution of compound D from Example 73 (0.40 g, 0.81 mmol) in CH₃ OH(50 ml) containing 10% Pt/C (150 mg) was hydrogenated at 50 psi for 3days. The catalyst was filtered, washed with CH₃ OH, and the filtratescombined and concentrated. The oily residue was purified by flashchromatography (Merck Silica gel, 25% acetone/hexane followed by 50%acetone/hexane). The product was obtained as a colorless oil (0.24g,60.0%).

R_(f) 0.35 (50% acetone/hexane) UV

B. (S)-4-[[2-[6-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

The diester from part A (0.22 g, 0.44 mmol) in dioxane (15 ml) wastreated with 1N NaOH (1.54 ml, 1.54 mmol) at room temperature and thenheated at 50° C. for 21 hours. The solvent was evaporated and theresidue was chromatographed twice on HP-20 resin, eluting first with H₂O (200 ml), followed by 25% MeOH/H₂ O (100 ml), 50% MeOH/H₂ O (150 ml)and finally MeOH (150ml). The collected product fractions wereevaporated, dissolved in H₂ O, filtered, frozen and lyophilized to giveExample 74 as a white lyophilate (0.106 g, 47.0%).

R_(f) 0.34 (8:1:1--CH₂ Cl₂ :CH₃ OH:HOAc), UV Analysis for C₂₄ H₃₁ NFPO₅Na₂ ×2.0 H₂ O: Calc'd C, 52.85; H, 6.47; N, 2.57; F, 3.48; P, 5.68 FoundC, 52.73; H, 6.65; N, 2.38; F, 3.70; P, 5.30

Example 75(S,E)-4-[[2-[4-(4-Fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-3-yl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A.3-Ethynyl-4-(4-fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-benzo[6,7]cyclohepta[1,2-b]pyridine

The vinyl dibromide compound D from Example 63 (3.520 gm, 6.8 mmol) wasadded as a solution of THF (4 ml) over 2.5 minutes to a -78° C. solutionof n-BuLi (2.5M in hexane, 5.46 ml, 13.66 mmol), in THF (20 ml). Thesolution was allowed to stir at -78° C. for 1.5 hours. Saturated NH₄ Clwas added to quench the reaction and the mixture warmed to 0° C. andsaturated NaHCO₃ added. The mixture was then warmed to room temperature,diluted with ether and the aqueous layer back-extracted with ether(twice). The organic layers were combined and washed with brine, thendried over MgSO₄, filtered and concentrated to afford a yellow oil, Theyellow oil was purified by flash chromatography on Merck silica gel in1% EtOAc in hexane. Fractions containing the product were pooled andconcentrated to give a white solid. The solid was recrystallized fromhexane as hard white crystals (2.108 gm, 87%).

m.p. 131°-132° C. Rf 0.43 (1% EtOAc in hexane)

B.(E)-3-(2-Iodoethenyl)-4-(4-fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-benzo-[6,7]cyclohepta[1,2-b]pyridine

A mixture of the acetylene prepared in part A (2.108 gm, 6.68 mmol), Bu₃SnH (3.507 gm, 12.03 mmol), and AIBN (0.0408 gm) was heated to 140° C.for 1.5 hours. Ether (20 ml) was added to the mixture after it hadcooled to room temperature. The solution was then treated with I₂ (3.49gm) and stirred at room temperature for 18 hours. The solution wasdiluted with ether, washed with 10% Na₂ SO₄ in saturated NaHCO₃ andbrine, then dried over MgSO₄, filtered and concentrated to a yellow oil.The oil was purified by flash chromatography on Merck silica gel in 1%EtOAc in hexane. Fractions containing product compound B were pooled andconcentrated to give a yellow solid. The solid was recrystallized fromhexane to afford product compound B as yellow crystals (2.363 gm, 80%).

m.p. 169°-170° C. TLC: Rf 0.55 (2% EtOAc in hexane)

C.(S)-4-[[2-[6-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

The vinyl iodide from part B (2.363 gm, 5.0 mmol) was added as a THFsolution (5 ml) over 3 minutes to a solution of t-BuLi (1.7M in pentane,5.90 ml, 10 mmol) in THF (10 ml) at -78° C. The solution was allowed tostir 1 hour at -78° C., then cooled to -100° C. and cannulated over 1.5minutes into a THF solution (20 ml) of the Example 57, part G chloridatealso cooled to -100° C. The resultant red-amber solution was stirred for45 minutes, then quenched with saturated NH₄ Cl (15 ml). The solutionwas warmed to 0° C. and saturated NaHCO₃ was added. The mixture wasdiluted with ether and the aqueous layer back-extracted with ether(twice). The organic layers were combined and washed with brine, thendried over Na₂ SO₄, filtered and concentrated to give an orange oil. Theoil was purified by flash chromatography on Merck silica gel in 40%EtOAc in hexane. Desired fractions were combined and evaporated toafford the product as a beige foam (1.408 gm, 39%).

TLC: Rf 0.36 (40% EtOAc in hexane)

D.(S)-4-[[2-[6-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

A THF solution (20 ml) of compound C (1.408 gm, 1.88 mmol) was treatedwith acetic acid (0.45 gm, 7.55 mmol) and then (Bu)₄ NF (1.0M in THF,5.64 ml, 5.64 mmol) and allowed to stir 16 hours at room temperature.The solution was diluted with EtOAc, then washed with saturated NaHCO₃,water, 1.5M HCl, water, and brine, then dried over MgSO₄, filtered andconcentrated to give a yellow oil. The oil was purified by flashchromatography on Merck silica gel in 50% acetone in hexane. Pureproduct fractions were pooled and concentrated to afford compound D as abeige foam (0.726 gm, 71%).

TLC: Rf 0.48 (50% acetone in hexane)

E.(S,E)-4-[[2-[4-(4-Fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-3-yl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A solution of NaOH (1.0M in water, 2.1 ml, 2.1 mmol) was added to asolution of compound D in dioxane (5 ml) and allowed to stir 19 hours atroom temperature. The solution was then concentrated to a white solid.The solid was dissolved in water and chromatographed on HP-20 resin,eluting first with water (200 ml), then with 50% MeOH in water (400 ml),then with MeOH (200 mol). The desired fractions were pooled andconcentrated. The residue was taken up in water and lyophilized to giveExample 75 as a fluffy white solid (0.375 gm, 97%).

TLC: Rf 0.68 (6:3:1, n-propanol:NH₄ OH:H₂ O) Elemental Analysis for C₂₉H₂₉ NFNa₂ PO₅ ×2.50 H₂ O: Calculated: C, 56.87; H, 5.59; N, 2.29; F,3.10; P, 5.06 Found: C, 56.53; H, 5.48; N, 2.38; F, 3.40; P, 5.26

Example 76(S)-4-[[2-[4-(4-Fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-3-yl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoidacid, disodium salt

A.(S)-4-[[2-[4-(4-Fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-benzo[6,7]-cyclohepta[1,2-b]pyridin-3-yl]ethyl]methoxyphosphinyl]-3-hydroxybutanoidacid, methyl ester

A mixture of compound D from Example 75 (0.347 g, 0.63 mmol) and 10%Pd/C (0.067 g, 0.063 mmol) in MeOH (50 ml) was purged with argon forfifteen minutes, then placed under a hydrogen pressure of 50 psi on aParr apparatus for 7 days. The solution was then filtered through a padof Celite® which was washed repeatedly with MeOH. The solution wasconcentrated and the white residue purified by flash chromatography onMerck silica gel in 40% acetone in hexane. After combining andconcentrating the desired fractions, the product A was obtained as awhite foam (0.295 gm, 85%).

TLC: Rf 0.44 (50% acetone in hexane)

B.(S)-4-[[2-[4-(4-Fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-3-yl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoidacid, disodium salt

A solution of the part A compound (0.295 g, 0.533 mmol) in dioxane (7ml) was treated with a solution of NaOH (1.0M in water, 1.60 ml, 1.60mmol) and allowed to stir at 50° C. for 3 hours. The solution was cooledto room temperature and concentrated to a white solid. The residue wasdissolved in water and chromatographed on HP-20 resin, eluting firstwith water (200 ml), then with 50% MeOH in water (400 ml), and then withMeOH (200 mol). The desired fractions were pooled and concentrated, theresidue was taken up in water and lyophilized to give Example 76 as afluffy white solid (0.285 gm, 94%).

TLC: Rf 0.66 (6:3:1, n-propanol:NH₄ OH:H₂ O) Elemental Analysis for C₂₉H₃₁ NFNa₂ PO₅ ×2.04 H₂ O: Calculated: C, 57.46: H, 5.83; N, 2.31; F,3.13; P, 5.11 Found: C, 57.59; H, 6.16; N, 2.33; F, 3.18; P, 5.38

Example 77(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-5,6-diphenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, methyl ester, monosodium salt

A solution of compound G from Example 56 (510 mg, 0.87 mmol) in CH₂ Cl₂(6 ml) was treated with BSTFA (277 μl, 269 mg, 1.05 mmol). Afterstirring at room temperature for 1.5 hours, the solution was treatedwith TMSBr (161 μl, 187 mg, 1.22 mmol). After 45 minutes, the mixturewas quenched by the addition of MeOH (500 μl) and the solution wasstirred for 15 minutes, then treated with TEA (250 μl), poured intoEtOAc and subsequently washed with 5% KHSO₄ (twice) and brine. Theorganic layer was dried (Na₂ SO₄), filtered and stripped to yield anoil, which was dissolved in cold Et₂ O (4 ml) and treated with asolution of adamantamine (147 mg, 0.97 mmol) in hexane (2 ml). Theresulting white solid (607 mg, 97% yield of the adamantamine salt ofExample 77) was collected by filtration and washed with cold Et₂ O.

A slurry of the amine salt (585 mg, 0.81 mmol) in a mixture of EtOAc (50ml) and H₂ O (7 ml) was treated dropwise with 1N HCl (0.82 ml, 0.82mmol) and the two clear layers were separated and the EtOAc layer waswashed with additional 5% KHSO₄ and brine, then dried (Na₂ SO₄),filtered and stripped. The residue (white foam) was dissolved in CH₂ Cl₂(4 ml) and treated with TEA (192 μl). After stirring at room temperaturefor 15 minutes, the solvent was stripped and the residue was azeotropedwith toluene. The resulting oily foam was dissolved in warm H₂ O (7 ml)and passed through an ion exchange column (Dowex AG-50-WX2 (Na⁺ form),23 ml wet), eluting with H₂ O. The desired fractions were pooled andlyophilized to give Example 77 (450 mg, 88%, 85% overall from 1) as awhite solid.

TLC R_(f) 0.61 (8:1:1--CH₂ Cl₂ :HOAc:MeOH) Analysis for C₃₃ H₃₀ FNNaO₅P×2.24 H₂ O: Calc'd C, 62.53; H, 5.48; N, 2.21; F, 3.00; P, 4.89 FoundC, 62.57; H, 5.15; N, 2.17; F, 3.02; P, 5.17

Example 78(S,E)-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, methyl ester, monosodium salt

A solution of compound C from Example 7 (315 mg, 0.616 mmol) in CH₂ Cl₂(6 ml) was treated with BSTFA (200 μl, 194 mg, 0.75 mmol). Afterstirring at room temperature for 1.25 hours, the solution was treatedwith TMSBr (115 μl, 133 mg, 0.87 mmol). After 40 minutes, the mixturewas quenched by the addition of MeOH (400 μl) and the solution wasstirred for 15 minutes, then treated with TEA (172 μl), poured into 5%KHSO₄ and extracted with EtOAc (3 times). The organic extract was washedwith brine, then dried (Na₂ SO₄), filtered and stripped to yield a wetsolid. The solid was slurried in cold Et₂ O and collected to give 201 mgof the free acid of Example 78. An additional 86 mg was obtained fromconcentration of the filtrate (total solids, 287 mg, 94%).

A slurry of the above solid (287 mg, 0.58 mmol) in CH₂ Cl₂ (8 ml) wastreated with TEA (121 μl). After stirring at room temperature for 15minutes, the colorless homogeneous solution was stripped and the residuewas azeotroped with toluene. The resulting white foam was dissolved inH₂ O and passed through an ion exchange column (Na⁺ form, 7 ml wet),eluting with H₂ O. The desired fractions were pooled and lyophilized togive Example 78 (300 mg, 89%, 84% overall from compound C from Example7) as a white solid.

TLC R_(f) 0.58 (8:1:1--CH₂ Cl₂ :HOAc:MeOH) Analysis for C₂₇ H₂₈ FNNaO₅P×2.0 H₂ O: Calc'd C, 58.37; H, 5.81; N, 2.52; F, 3.42; P, 5.57 Found C,58.20; H, 5.46; N, 2.56; F, 3.47; P, 5.82

Example 79(S)-4-[[[4-(4-Fluorophenyl)-6-methyl-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A. 3-(4-Fluorophenyl)-1-methyl-2-propen-1-one

A mixture of 4-fluorobenzaldehyde (4.53 ml, 42.0 mmol; Aldrich) and1-triphenylphosphoranylidene-2-propanone (11.1 g, 35.0 mmol; Aldrich) inCH₂ Cl₂ was refluxed for 48 hours. After cooling to room temperature,the reaction mixture was concentrated and purified by flashchromatography (Merck silica gel, 10% EtOAc/hexane) to afford compound Aas a colorless oil (4.95 g, 78.4%).

R_(f) 0.34 (20% EtOAc/hexane), UV

B. β-(4-Fluorophenyl)-α-(2-methyl-1-oxopropyl)-Δ-oxohexanoic acid, ethylester

A solution of compound A (5.3 g, 32.3 mmol) in ether (80 ml) was addeddropwise to a mixture of ethyl isobutyrylacetate (10.42 ml, 64.6 mmol)and KOH (0.15 g, 2.7 mmol) in absolute ethanol (1.5 ml). The reactionmixture was stirred at room temperature for 24 hours, acidified to pH 5with glacial HOAc, washed twice with H₂ O, then saturated NaHCO₃, dried(MgSO₄) and concentrated. The yellow oily residue was purified by flashchromatography (Merck silica gel, 10% EtOAc/hexane) to afford compound Bas a colorless oil (5.8 g, 56.0%, mixture of diastereomers).

R_(f) 0.32+0.36 (25% EtOAc/hexane), UV

C. 4-(4-Fluorophenyl)-6-methyl-2-(1-methylethyl)-3-pyridinecarboxylicacid, ethyl ester

A mixture of compound B (5.8 g, 18.0 mmol), ammonium acetate (4.16 g,54.0 mmol) and copper (II) acetate (8.98 g, 45.0 mmol) in glacial aceticacid (60 ml) was heated at 115° C. for 2.5 hours. The reaction mixturewas cooled and carefully poured into an ice cold mixture of concentratedNH₄ OH (80 ml) and H₂ O (100 ml). The mixture was extracted with ether(twice) and the ether extracts were washed with H₂ O (twice) and brine,then dried (MgSO₄), filtered and concentrated. The dark oily residue waspurified by flash chromatography (10% EtOAc/hexane) to afford compound Cas a colorless oil (2.5 g, 46.3%).

R_(f) 0.54 (20% EtOAc/hexane), UV

D. 4-(4-Fluorophenyl)-6-methyl-2-(1-methylethyl)-3-pyridinemethanol

A cold (0° C.) solution of ester (2.42 g, 8.03 mmol) in dry THF (55 ml)was treated with LiAlH₄ (0.91 g, 24.10 mmol). Ten minutes after theaddition the cooling bath was removed and the reaction mixture wasstirred at room temperature for 24 hours. The reaction mixture wascooled to 0° C. and carefully quenched in succession with 0.91 ml of H₂O in THF (10 ml), then 0.91 ml 15% NaOH and finally 2.0 ml H₂ O. Theprecipitated aluminum salts were filtered and washed with EtOAc andether. The filtrate was washed with H₂ O and brine, dried (Na₂ SO₄),filtered and concentrated under reduced pressure to give an off-whitesolid residue. Recrystallization from hexane afforded compound D as awhite solid (1.80 g, 86.0%).

m.p. 154°-155° C. R_(f) 0.4 (20% EtOAc/hexane), UV Anal. Calc'd for C₁₆H₁₈ NFO: Calc'd C, 74.10; H, 7.00; N, 5.40; F, 7.33 Found C, 74.15; H,7.14; N, 5.25; F, 7.30

E.4-(4-Fluorophenyl)-6-methyl-2-(1-methylethyl)-3-pyridinecarboxaldehyde

A -78° C. solution of oxalyl chloride (0.73 ml, 8.32 mmol) in CH₂ Cl₂(80 ml) was treated dropwise with a solution of dry DMSO (1.18 ml, 16.65mmol) in CH₂ Cl₂ (10 ml). After 15 minutes, a solution of alcohol D(1.80 g, 6.94 mmol) in CH₂ Cl₂ (10 ml) was added dropwise to the abovesolution. After 20 minutes, triethylamine (5.80 ml, 41.64 mmol) wasadded and the mixture was stirred at -78° C. for 20 minutes and thenwarmed to room temperature. After 1 hour, the reaction was quenched withH₂ O and diluted with ether. The layers were separated and aqueous layerwas extracted with CH₂ Cl₂ (twice). The combined organic solutions werewashed with H₂ O (twice) and brine, then dried (MgSO₄), filtered andconcentrated under reduced pressure. The oily residue was purified byflash chromatography (Merck silica gel, 10% EtOAc/hexane), affording thealdehyde E as a colorless oil (1.68 g, 94.5%).

R_(f) 0.65 (20% EtOAc/hexane), UV

F.3-(2,2-Dibromoethenyl)-4-(4-fluorophenyl)-6-methyl-2-(1-methylethyl)pyridine

A solution of carbon tetrabromide (3.24 g, 9.79 mmol) in CH₂ Cl₂ (10 ml)was added dropwise over a 5-minute period to a cold (0° C.) solution ofaldehyde E (1.68 g, 6.52 mmol) and triphenylphosphine (5.13 g, 19.56mmol) in CH₂ Cl₂ (60 ml). The mixture was stirred at 0° C. for 20minutes and then at room temperature for 1 hour. The solution wasquenched with saturated NaHCO₃ and extracted twice with CH₂ Cl₂. Thecombined organic layers were dried (Na₂ SO₄), filtered, concentrated to1/3 volume and applied on Merck silica gel column (50% CH₂ Cl₂ /hexane).Flash chromatography afforded compound F as a colorless oil (2.68 g,100.0%).

R_(f) 0.50 (10% EtOAc/hexane), UV

G.(S)-4-[[[4-(4-Fluorophenyl)-6-methyl-2-(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

A solution of dibromide F (2.60 g, 6.31 mmol) in THF (20 ml) at -78° C.was treated with n-BuLi (2.5M in hexane, 5.30 ml, 13.25 mmol) over a1-minute period. The dark blue reaction mixture was stirred for 30minutes at -78° C. and then transferred via cannula to a -78° C.solution of the phosphonochloridate from Example 57, part G in THF (20ml). The dark-brown reaction mixture was stirred at -78° C. for 30minutes and then quenched with 50% saturated NH₄ Cl. After warming toroom temperature, the solution was diluted with H₂ O and poured intosaturated NaHCO₃. The layers were separated and the aqueous layer wasextracted once with ether. The combined organic layers were washed withbrine, dried (Na₂ SO₄), filtered and concentrated under reducedpressure. The dark oily residue was purified by flash chromatography(Merck silica gel, 30% EtOAc/hexane) to afford compound G as a paleyellow oil (2.58 g, 60.0%).

R_(f) 0.19 (30% EtOAc/hexane), UV

H.(S)-4-[[[4-(4-Fluorophenyl)-6-methyl-2-(1-methylethyl)-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

To a solution of acetylinic phosphonate G (2.50 g, 3.65 mmol) in THF (15ml) was added HOAc (0.83 ml, 14.60 mmol), followed bytetra-n-butylammonium fluoride (1.0M in THF, 10.95 ml, 10.95 mmol). Thereaction mixture was stirred at room temperature under argon for 24hours. The solution was diluted with EtOAc and washed three times with5% KHSO₄. The pooled aqueous layers were back-extracted twice with EtOAcand the combined organic extracts were dried (Na₂ SO₄), filtered andconcentrated under reduced pressure. The dark oily residue was dissolvedin ether (a few drops of THF were added to obtain a clear solution),cooled to 0° C. and treated with excess diazomethane in ether for 20minutes. The excess diazomethane was destroyed by the addition of HOAc.Solvent removal gave a dark oily residue, which was purified by flashchromatography (Merck silica gel, 30% acetone/hexane). The product H wasobtained as as a colorless oil (0.68 g, 42.5%).

R_(f) 0.22 (40% acetone/hexane) UV

I.(S)-4-[[[4-(4-Fluorophenyl)-6-methyl-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

The diester H (0.20 g, 0.44 mmol) in dioxane (5 ml) was treated with 1NNaOH (1.54 ml, 1.54 mmol) at room temperature and then heated at 50° C.for 4 hours. The reaction mixture was concentrated and the residue waschromatographed on HP-20 resin, eluting first with H₂ O (200 ml),followed by 25% MeOH/H₂ O (150 ml), 50% MeOH/H₂ O (200 ml) and finallyMeOH (100 ml). The collected product fractions were evaporated,dissolved in H₂ O, filtered, frozen and lyophilized to give Example 79as a white lyophilate (0.17 g, 85.5%).

m.p. >165° C. (decomposition) R_(f) 0.1 (8:1:1--CH₂ Cl₂ :CH₃ OH:HOAc),UV Analysis for C₂₁ H₂₁ NFPO₅ Na₂ ×3.0 H₂ O: Calc'd C, 48.75; H, 5.26;N, 2.71; F, 3.67; P, 5.99; Found C, 48.66; H, 4.90; N, 2.46; F, 3.53; P,5.67

Example 80(S)-4-[[[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, methyl ester, monosodium salt

A solution of compound H from Example 53 (666 mg, 1.27 mmol) in CH₂ Cl₂(7 ml) was treated with BSTFA (380 μl, 368 mg, 1.43 mmol). Afterstirring at room temperature for 1.5 hours, the solution was treatedwith TMSBr (185 μl, 214.6 mg, 1.4 mmol). After 30 minutes, additionalTMSBr (80 μl) was added and stirring was continued for 15 minutes. Themixture was quenched by the addition of MeOH (500 μl) and the solutionwas stirred for 15 minutes, then treated with TEA (300 μl), poured intoEtOAc and subsequently washed with 5% KHSO₄ (twice) and brine. Theorganic layer was dried (Na₂ SO₄), filtered and stripped to yield anoily foam which was dissolved in cold Et₂ O (8 ml) and treated with asolution of adamantamine (195 mg, 1.29 mmol) in hexane (4 ml). Theresulting solid (776 mg, 92% yield of the adamantamine salt of Example80, mp. 226°-228° C.) was collected by filtration and washed with coldEt₂ O.

The amine salt (747 mg, 1.13 mmol) was slurried between 5% KHSO₄ (50 ml)and EtOAc (50 ml) and treated with 1N HCl (1.1 ml, 1.1 mmol) and thelayers were separated and the EtOAc layer was washed with additional 5%KHSO₄ and filtered. The filtrate was washed with brine, then dried (Na₂SO₄), filtered and stripped. The residue (white foam) was dissolved inCH₂ Cl₂ (8 ml) and treated with TEA (265 μl). After stirring at roomtemperature for 10 minutes, the solvent was stripped and the residue wasazeotroped with toluene. The resulting oily foam was dissolved in H₂ Oand passed through an ion exchange column (Dowex AG-50-WX2 (Na⁺ form),20 ml wet), eluting with H₂ O. The desired fractions were pooled andlyophilized to give Example 80 (550 mg, 92%, 85% overall from compoundH, Example 53) as a white solid.

TLC R_(f) 0.27 (8:1:1--CH₂ Cl₂ :HOAc:MeOH) Analysis for C₂₈ H₂₈ FNNaO₅P×2.40 H₂ O: Calc'd C, 58.51; H, 5.75; N, 2.44; F, 3.31; P, 5.39 FoundC, 58.60; H, 5.30; N, 2.30; F, 3.55; P, 5.09

Example 81(S)-4-[[2-[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, methyl ester, monosodium salt

A.3-(1-Ethynyl)-4-(4-fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenylpyridine

To a solution of n-BuLi (2.5M in hexanes, 4.00 ml, 10.0 mmol) in dry THF(8 ml) at -78° C. was added a solution of compound F from Example 53(2.267 gm, 4.63 mmol) in dry THF (8 ml) over a 5-minute period. Afterstirring at -78° C. for one hour, the pale green solution was quenchedwith saturated NH₄ Cl and warmed to room temperature. The mixture wasdiluted with H₂ O, extracted with Et₂ O and the Et₂ O extract was washedwith brine, dried (Na₂ SO₄), filtered and stripped to yield a solid. Theresidue was recrystallized from hot EtOAc/hexane to afford acetylene A(1.169 gm) as a white solid. An additional 251 mg of product wasobtained by recrystallization of the mother liquor to give a total of1.420 gm (93%) of analytically pure material.

m.p. 178.0°-178.5° C. TLC R_(f) 0.43 (10% EtOAc in hexane) Analysis forC₂₃ H₂₀ FN×0.11 H₂ O: Calc'd C, 83.37; H, 6.15; N, 4.23; F, 5.73 FoundC, 83.25; H, 5.98; N, 4.35; F, 5.89

B.4-(4-Fluorophenyl)-3-(2-iodoethenyl)-5-methyl-2-(1-methylethyl)-6-phenylpyridine

A mixture of compound A (1.355 gm, 4.1 mmol) and AIBN (20 mg) intri-n-butylstannyl hydride (2.0 ml) was rapidly heated to 120° C. After4 minutes of heating, the mixture was treated with additional Bu₃ SnH(0.6 ml) and the temperature of the reaction was raised to 140° C.Approximately 20 mg of AIBN was added to the reaction mixture one andtwo hours after heating was initiated. After 3 hours, the mixture wascooled to room temperature, diluted with Et₂ O (50 ml) and treated withsolid I₂ (3.50 gm, 13.8 mmol). The dark reaction mixture was stirred for45 minutes, then poured into a 50% saturated NaHCO₃ solution containing6.7 gm Na₂ S₂ O₃. The layers were shaken and separated. The ethereallayer was washed successively H₂ O, 1.7M NH₄ OH, and brine, then dried(Na₂ SO₄), filtered and stripped to yield a wet solid. The solid wastaken up in Et₂ O, filtered through Celite® and stripped. The residuewas recrystallized from hot hexane to give compound B (1.335 gm) aswhite crystals. The mother liquor was flashed (Merck SiO₂, 5% EtOAc inhexane) and the desired fractions were pooled, stripped, recrystallized,and pooled with the above solid to give a total of 1.637 gm (87%) ofcompound B.

m.p. 148.5°-150.0° C. TLC R_(f) 0.13 (2% EtOAC in hexane)

C.(S)-4-[[2-[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

A solution of vinyl iodide B (1.500 gm, 3.28 mmol) in THF (6 ml) wasadded over a 4-minute period to a -78° C. solution of t-butyllithium(1.7M in pentane, 4.05 ml, 6.9 mmol) in THF (10 ml). The resultingsolution was stirred for 25 minutes and then cooled to minus 100° C. Thevinyl anion solution was added over a 30-second period to a -100° C.solution of the phosphonochloridate from Example 4, part C in THF (15ml). The resulting orange mixture was stirred at -100° C. for 40minutes, then quenched with 50% saturated NH₄ Cl. The solution waswarmed to room temperature, diluted with H₂ O, and poured into saturatedNaHCO₃. The aqueous phase was extracted twice with Et₂ O. The combinedEt₂ O layers were washed with brine, dried (Na₂ SO₄), filtered andstripped. The resulting yellow oil was chromatographed (flash, MerckSiO₂, 50% EtOAc in hexane) to afford compound C as an off-white foam(778 mg, 31%).

TLC R_(f) 0.18 (40% EtOAc in hexane)

D.(S)-4-[[2-[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]-3-butanoicacid, methyl ester

A solution of compound C (768 mg, 1.0 mmol) in THF (6 ml) was treatedwith HOAc (286 μl, 300 mg, 5.0 mmol) and tetra-n-butylammonium fluoride(1.0M in THF, 5.0 ml, 5.0 mmol). After stirring at room temperature for22 hours, the solution was poured into saturated NaHCO₃ and extractedwith EtOAc. The EtOAc extract was washed with brine, dried (Na₂ SO₄),filtered, and stripped to give an oil, which was subsequentlychromatographed (flash, Merck SiO₂, 50% acetone in hexane). Compound D(425 mg, 81%) was obtained as an oil.

TLC R_(f) 0.34 (1:1 acetone:hexane)

E.(S)-4-[[2-[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, methyl ester, monosodium salt

A solution of compound D (420 mg, 0.80 mmol) in CH₂ Cl₂ (6 ml) wastreated with BSTFA (255 μl, 247 mg, 0.96 mmol). After stirring at roomtemperature for 1.5 hours, the solution was treated with TMSBr (158 μl,183 mg, 1.2 mmol). After 45 minutes, MeOH (400 μl) was added, andstirring was continued for an additional 15 minutes. The solution wastreated with TEA (180 μl), poured into EtOAc and subsequently washedwith 5% KHSO₄ (twice) and brine. The organic layer was dried (Na₂ SO₄),filtered and stripped to yield an oil, which was dissolved in cold Et₂ O(4 ml) and treated with a solution of adamantamine (127 mg, 0.84 mmol)in hexane (3 ml). The resulting solid (279 mg, 53% yield of salt) wascollected by filtration and washed with cold Et₂ O.

The salt was slurried in 5% KHSO₄ and EtOAc and treated with 1N HCl(0.40 ml) and the layers were separated and the EtOAc layer was washedwith additional 5% KHSO₄ and brine, then dried (Na₂ SO₄), filtered andstripped. The residue was dissolved in CH₂ Cl₂ (3 ml) and treated withTEA (60 μl). After stirring at room temperature for 10 minutes, thesolvent was stripped and the residue was azeotroped with toluene (3 ml).The resulting acid was dissolved in H₂ O and passed through an ionexchange column (Na⁺ form, 10 ml wet), eluting with H₂ O. The desiredfractions were pooled and lyophilized to give Example 81 (136 mg, 30%overall) as a white solid.

TLC Rf 0.51 (8:1:1--CH₂ Cl₂ :HOAc:MeOH) Analysis for C₂₈ H₃₀ FNNaO₅P×1.80 H₂ O: Calc'd C, 59.42; H, 5.98; N, 2.48 Found C, 59.35; H, 5.67;N, 2.55

Example 82(S)-4-[[2-[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A solution of Example 81 (61.4 mg, 0.11 mmol) in H₂ O (6 ml) was treatedwith 1N NaOH (250 μl, 0.25 mmol) at room temperature for 30 minutes andthe mixture was subsequently heated at 55° C. for 30 minutes. Thesolution was chromatographed directly on HP-20, eluting in successionwith H₂ O (100 ml) and 50% MeOH in H₂ O (150 ml). The desired fractionswere pooled and evaporated and the residue was taken up in H₂ O andlyophilized to give Example 82 (64 mg, 100%) as a white solid.

TLC R_(f) 0.72 (7:2:1, i-PrOH, NH₄ OH, H₂ O) Analysis for C₂₇ H₂₇ FNNa₂O₅ P×2.45 H₂ O: Calc'd: C 55.38 H 5.49 N 2.39 Found: C 55.40 H 5.49 N2.15

Example 83(S)-4-[[2-[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A.(S)-4-[[2-[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

A mixture of compound D from Example 81 (494 mg, 0.94 mmol) and Pd oncarbon (10% Pd on C, 110 mg) in MeOH (20 ml) was shaken under 50 psi ofH₂ for 3 days. The solution was filtered, stripped, and chromatographed(flash, Merck SiO₂, 50% acetone in hexane) to give compound A (419 mg,85%) as a colorless oil.

TLC R_(f) 0.36 (1:1--acetone:hexane)

B.(S)-4-[[2-[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A solution of compound A (405 mg, 0.77 mmol) in dioxane (5 ml) wastreated with 1N NaOH (2.7 ml, 2.7 mmol) and the mixture was stirred at60° C. for 1.75 hours. The solvent was evaporated and the residue waschromatographed on HP-20, eluting in succession with H₂ O and 50% MeOHin H₂ O. The desired fractions were pooled and evaporated, and theresidue was taken up in H₂ O and lyophilized to give Example 78 (360 mg,77%) as a white solid.

m.p. 293° C. (decomp.); [a]_(D) =+0.8° (MeOH, c=0.49) TLC R_(f) 0.10(8:1:1--CH₂ Cl₂ :HOAc:MeOH) Microanalysis for C₂₇ H₂₉ FNNa₂ O₅ P×3.69 H₂O: Calc'd: C 53.17 H 6.01 N 2.30 F 3.11 P 5.08 Found: C 53.17 H 5.62 N2.31 F 3.20 P 5.10

Example 84(S)-4-[[[2-Ethyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A. 2-[(4-Fluorophenyl)methylene]-3-oxopentanoic acid, methyl ester

A mixture of para-fluorobenzaldehyde (37.98 gm, 306 mmol),3-oxopentanoic acid, methyl ester (39.78 gm, 306 mmol), piperidine (2.60gm, 30.6 mmol) and HOAc (0.555 gm, 9.2 mmol) was allowed to reflux inbenzene (150 ml) 7 hours under argon. The solution was cooled to roomtemperature, then diluted with ether and washed with 2% HCl, saturatedNaHCO₃, water, and brine, then dried over MgSO₄, filtered andconcentrated to give a yellow oil. The oil was purified by distillation(bp=144° C. at 2.7 mm Hg) to give the title compound as a yellow oil(50.612 gm, 70%).

Microanalysis for C₁₃ H₁₃ FO₃ : Calc'd: C 66.09 H 5.55 F 8.04 Found: C66.45 H 5.59 F 7.79

B. β-(4-Fluorophenyl)-γ-methyl-α-(1-oxopropyl)-Δ-oxobenzenepentanoicacid, ethyl ester

Propiophenone (5.68 gm, 42.37 mmol) was added dropwise to a solution ofLiN(TMS)₂ (1M in THF, 42.37 ml, 42.37 mmol) cooled to -78° C. in THF (50ml) and stirred 1 hour. Compound A (8.00 gm, 33.90 mmol) was then addeddropwise as a solution in THF (5 ml) over two minutes. The solution wasallowed to stir for one hour at -78° C., then warmed to 0° C. andstirred for an additional 30 minutes. The reaction was then quenchedwith NH₄ Cl and warmed to room temperature. The solution was dilutedwith ether and EtOAc and the organic layer washed with water and brine,then dried over Na₂ SO₄, filtered and concentrated to give a yellow oil.Excess propriophenone was removed by distillation under vacuum (104° C.at 1 mm Hg). The pot residue, compound B, was used directly in the nextreaction.

C. 2-Ethyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinecarboxylicacid, ethyl ester

NH₄ OAc (7.84 gm, 102 mmol) and Cu(OAc)₂ (16.92 gm, 84.7 mmol) wereadded to an acetic acid solution (75 ml) of crude 1,5 diketone B (12.543gm, 33.9 mmol) and the mixture allowed to reflux 16 hours while stirringunder argon. The solution was then poured into an ice-cold solution ofNH₄ OH/H₂ O (100 ml/150 ml). The mixture was extracted with ether andEtOAc and the organic layer washed with water and saturated NaCl, thendried over MgSO₄, filtered and concentrated to afford a brown oil. Theoil was purified by flash chromatography on Merck silica in 10-15% EtOAcin hexane. The desired fractions were pooled and concentrated to give ared solid. Upon recrystallization of the solid from EtOAc/hexane,product C was obtained as hard reddish crystals (7.540 gm, 61%).

m.p. 84°-86° C. TLC: Rf 0.57 (15% EtOAc in hexane) Elemental Analysisfor C₂₃ H₂₂ NFO: Calc'd: C 76.01 H 6.10 N 3.86 F 5.23 Found: C 75.63 H5.78 N 3.97 F 5.38

D. 2-Ethyl-4-(4-Fluorophenyl)-5-methyl-6-phenyl-3-pyridinemethanol

A THF solution (75 ml) of ester C (7.540 gm, 20.8 mmol) was cooled to 0°C. and treated with LiAlH₄ (2.36 gm, 62.3 mmol). After stirring 15minutes at 0° C., the solution was warmed to room temperature andstirred for 16 hours. The solution was cooled to 0° C. and quenched bydropwise addition of 2.36 ml of water, followed by 2.36 ml of 15% NaOH,then 7.0 ml water. The aluminum paste was filtered out of solution andthe filtrate was concentrated to afford alcohol D as a white solid(6.106 gm, 99.6%).

m.p. 180°-181° C. TLC: Rf 0.46 (40% EtOAc in hexane)

E. 2-Ethyl-4-(4-Fluorophenyl)-5-methyl-6-phenyl-3-pyridinecarboxaldehyde

Tetrapropylammonium perruthenate (0.352 gm, 1.00 mmol) was added to aCH₂ Cl₂ solution (215 ml) of alcohol D (5.455 gm, 18.5 mmol) and4-Methylmorpholine-N-oxide (4.01 g, 34.2 mmol), stirring over 4 angstromsieves (10.85 gm) at room temperature. Forty-five minutes later, thereaction mixture was diluted with ether and filtered through a Celite®pad. The pad was washed repeatedly with ether and EtOAc. The solutionwas concentrated to give a dark oil which was purified by flashchromatography on Merck silica gel in 5% EtOAc in hexane. The desiredfractions were combined and concentrated to give a yellow solid. Thesolid was recrystallized from hexane to afford product E as pale yellowneedles (4.393 gm, 81%).

m.p. 97°-98° C. Elemental Analysis for C₂₁ H₁₈ NFO: Calc'd: C 78.97 H5.68 N 4.39 F 5.95 Found: C 79.03 H 5.52 N 4.35 F 5.82

F. 2-Ethyl-4-(4-Fluorophenyl)-5-methyl-6-phenyl-3-pyridinecarboxaldehyde

A solution of CBr₄ (7.57 gm, 22.5 mmol) in methylene chloride solution(30 ml) was added dropwise over 30 minutes to a solution of the aldehydeE (4.393, 15 mmol) and triphenylphosphine (12.59, 48 mmol) in methylenechloride (100 ml), which was stirring under argon at 0° C. The solutionwas stirred at 0° C. for an additional 30 minutes, then warmed to roomtemperature. Saturated NaHCO₃ was then added to quench the reaction. Theorganic layer was washed with brine, then dried over Na₂ SO₄, filteredand concentrated to about 20 ml. The solution was purified by flashchromatography on Merck silica gel in 15-25% EtOAc in hexane. Thedesired fractions were pooled and concentrated to afford a yellowishsolid, which was recrystallized from boiling hexane to afford compound Fas fine white needles (6.019 gm, 89%).

m.p. 137°-138° C. TLC: Rf 0.50 (5% EtOAc in hexane) Elemental Analysisfor C₂₂ H₁₈ NBr₂ F: Calc'd: C 55.61 H 3.82 N 2.95 Br 33.63 F 4.00 Found:C 55.89 H 3.59 N 2.93 Br 33.97 F 4.20

G. 2-Ethyl-3-ethynyl-4-(4-fluorophenyl)-5-methyl-6-phenylpyridine

A solution of vinyl dibromide F (6.019 gm, 13.4 mmol) in THF (7 ml) wasadded dropwise to a solution of n-BuLi (2.5M in hexane, 11.2 ml, 28.1mmol) in THF (40 ml), stirring at -78° C. under argon. The solution wasallowed to stir 1 hour at -78° C., then quenched with saturated NH₄ Cland warmed to 0° C., after which saturated NaHCO₃ was added. The mixturewas diluted with ether, the organic layer washed with brine, then driedover Na₂ SO₄, filtered and concentrated to give a yellow oil. The oilwas purified by flash chromatography on Merck silica gel in 1% EtOAc inhexane. Pure product fractions were combined and concentrated to affordcompound G as a white solid (3.568 gm, 85%).

TLC: R_(f) 0.48 (1% EtOSc in hexane) Elemental Analysis for C₂₂ H₁₈ NF:Calc'd: C 83.31 H 5.78 N 4.42 F 5.99 Found: C 83.40 H 5.65 N 4.33 F 5.96

H.(S)-4-[[[2-Ethyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

A solution of acetylene G (0.500 gm, 1.52 mmol) in THF (10 ml) was addeddropwise to a solution of n-BuLi (2.5M in hexane, 0.67 ml, 1.67 mmol) inTHF (15 ml) stirring at -78° C. under argon. The solution was allowed tostir 45 minutes at -78° C., then cannulated into a THF solution (15 ml)of the chloridate from Example 57, part G, which had also been cooled to-78° C. The solution was stirred for 30 minutes at -78 ° C., thenquenched with saturated NH₄ Cl and warmed to 0° C., after whichsaturated NaHCO₃ was added. The solution was diluted with ether and theorganic layer was washed with brine, dried over Na₂ SO₄, filtered andconcentrated to give a dark orange oil. The oil was purified by flashchromatography on Merck silica gel in 40% EtOAc in hexane. The desiredfractions were combined and concentrated to afford compound H as ayellowish oil (0.550 gm, 46%).

TLC: Rf 0.52 (50% acetone in hexane)

I.(S)-4-[[[2-Ethyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

(Bu)₄ NF (1M in THF, 2.21 ml, 2.21 mmol) was added to a solution ofsilyl ether H (0.550 gm, 0.736 mmol) and HOAc (0.176 gm, 2.94 mmol) inTHF (20 ml) under argon and allowed to stir 19 hours at roomtemperature. The reaction mixture was diluted with EtOAc, then washedwith 5% KHSO₄ (three times). The aqueous layers were extracted withEtOAc (three times). The organic layers were pooled and washed withbrine, then dried over Na₂ SO₄, filtered and concentrated to afford abrown oil. The oil was dissolved in ether (15 ml) and treated withexcess CH₂ N₂. Excess CH₂ N₂ was removed with a stream of argon, and thesolution was concentrated to give a brown-yellow oil. The oil waspurified by flash chromatography on Merck silica gel in 50% acetone inhexane. The desired fractions were pooled and concentrated to afford thetitle compound as a clear oil (0.200 gm, 53%).

TLC: Rf 0.52 (50% acetone in hexane)

J.(S)-4-[[[2-Ethyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

Di-ester I (0.200 gm, 0.393 mmol) was dissolved in dioxane (10 ml) andtreated with NaOH (1M in H₂ O, 1.18 ml, 1.18 mmol). The solution wasthen heated to 55° C. and allowed to stir 2 hours and 15 minutes. Thesolution was concentrated to a yellowish solid. The solid was dissolvedin water and chromatographed on HP-20 resin, eluting first with water(200 ml), then with 50% MeOH in water (400 ml), and finally MeOH (200ml). The desired fractions were pooled and concentrated, and theresultant white solid was dissolved in water and lyophilized to giveExample 84 as a fluffy, pale yellow solid (0.180 gm, 87%).

m.p. 310° C. (decomp) Elemental Analysis for C₂₆ H₂₃ NFNa₂ PO₅ ×2.00 H₂O: Calc'd: C 55.63 H 4.85 N 2.50 F 3.38 P 5.52 Found: C 55.52 H 4.67 N2.55 F 3.33 P 5.45 Optical Rotation: [a]_(D) =+8.1° (MeOH, c=3.45 mg/ml)

Example 85(S,E)-4-[[2-[2-Ethyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A.1-Ethyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-[2-(tributylstannyl)ethenyl]pyridine

A mixture of tri-n-butyltin hydride (4.27 gm, 14.6 mmol), acetylene Gfrom Example 84 (2.560 gm, 8.14 mmol) and AIBN (0.050 gm) was heated to140° C. for 30 minutes. The solution was then cooled to room temperatureand diluted with ether (30 ml). Iodine (4.25 gm, 16.73 mmol) was addedand the solution allowed to stir 16 hours at room temperature.Additional iodine (2.00 gm, 7.87 mmol) was added to the solution, whichstirred for 2 more hours. The solution was then quenched with 10% Na₂ S₂O₃ in saturated NaHCO₃. The solution was diluted with ether, washed with10% Na₂ S₂ O₃ in saturated NaHCO₃ (twice) and brine, then dried over Na₂SO₄, filtered and concentrated to give a dark brown residue. The oil waspurified by flash chromatography on Merck silica gel in 60% CH₂ Cl₂ inhexane. The desired fractions were combined and concentrated to give awhite solid. The white solid was recrystallized from hexane to affordproduct A as white crystals (2.565 gm, 73%).

m.p. 124°-126° C. TLC: Rf 0.27 (2% EtOAc in hexane) Elemental Analysisfor C₂₂ H₁₈ NF×0.10 H₂ O: Calc'd: C 83.31 H 5.78 N 4.42 F 5.99 Found: C83.40 H 5.65 N 4.33 F 5.96

B.(S,E)-4-[[2-[2-Ethyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

A solution of vinyl iodide A (1.639 gm, 3.70 mmol) in THF (7 ml) wasadded dropwise over 5 minutes to a solution of n-BuLi (1.7M in pentane,4.35 ml, 7.4 mmol) in THF (10 ml) cooled to -78° C. stirring underargon. The solution was allowed to stir 15 minutes at -78° C., thencooled to -100° C. and cannulated over 12 minutes into a THF solution(15 ml) of the chloridate from Example 57, part G, also cooled to -100°C. The solution was stirred 20 minutes at -100° C., then quenched withsaturated NH₄ Cl and warmed to 0° C., and then saturated NaHCO₃ wasadded to the solution. The solution was diluted with ether and theorganic layer was washed with brine, then dried over Na₂ SO₄, filteredand concentrated to give a dark orange oil. The oil was purified byflash chromatography on Merck silica gel in 50% EtOAc in hexane. Thedesired fractions were combined and evaporated to afford compound B as awhite, fluffy solid (0.985 gm, 36%).

TLC: R_(f) 0.50 (45% EtOAc in hexane)

C.(S,E)-4-[[2-[2-Ethyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

(Bu)₄ NF (1M in THF, 3.94 ml, 3.94 mmol) was added to a solution ofsilyl ether B (0.985 gm, 1.31 mmol) and HOAc (0.315 gm, 5.24 mmol) inTHF (20 ml) and allowed to stir 15 hours at room temperature. AdditionalTBAF (1.30 ml, 1.30 mmol) and HOAc (0.100 ml, 1.75 mmol) were added, andthe reaction mixture was allowed to stir under argon for another 3hours. The solution was diluted with EtOAc and washed with 5% KHSO₄(three times). The aqueous layers were extracted with EtOAc (twice) andthe organic layers were combined and washed with brine, then dried overNa₂ SO₄, filtered and concentrated to give a yellow oil. The oil waspurified by flash chromatography on Merck silica gel in 50% acetone inhexane. The desired fractions were pooled and concentrated to affordcompound C as a clear oil (0.430 gm, 64%).

TLC: Rf 0.54 (50% acetone in hexane)

D.(S,E)-4-[[2-[2-Ethyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

NaOH (1M in H₂ O, 1.29 ml, 1.29 mmol) was added dropwise to compound C(0.219 gm, 0.428 mmol) in dioxane (10 ml) and warmed to 60° C. andstirred 3 hours. Additional NaOH (1M in H₂ O, 0.40 ml, 0.40 mmol) wasadded to the solution, which stirred for another hour at 60° C. Themixture was then concentrated to a white solid. The solid was dissolvedin water and chromatographed on HP-20 resin, eluting first with water(200 ml), then with 50% MeOH in water (400 ml), and finally, MeOH (200ml). The desired fractions were pooled, concentrated, and the resultantwhite solid dissolved in water and lyophilized to give Example 85 as afluffy white solid (0.175 gm, 78%).

m.p. 305° C. (decomp) TLC: Rf 0.69 (6:3:1, n-propanol:NH₄ OH:H₂ O)Elemental Analysis for C₂₆ H₂₅ NFNa₂ PO₅ ×1.75 H₂ O: Calc'd: C 55.86 H5.01 N 2.51 F 3.40 P 5.54 Found: C 55.86 H 5.01 N 2.51 F 3.54 P 5.45Optical Rotation: [a]_(D) =+1.8° (MeOH, c=4.8 mg/ml)

Example 86(S)-4-[[[4-(4-Fluorophenyl)-5,6-dihydro-2-(1-methylethyl)benzo[h]quinolin-3-yl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A.β-(4-Fluorophenyl)-1,2,3,4-tetrahydro-α-(2-methyl-1-oxopropyl)-1-oxo-2-naphthalenepropanoicacid, ethyl ester

A -78° C. solution of lithium bis(trimethylsilyl)amide (1M in THF, 33.5ml, 33.6 mmol) in THF (70 ml) was treated dropwise with a solution of3,4-dihydro-1(2H)-naphthalenone (4.46 ml, 33.6 mmol, Aldrich) in THF (10ml). After one hour, a solution of the compound from Example 53, part A(6.96 gm, 28.0 mmol) in THF (5 ml) was added to the solution. Themixture was stirred at -78° C. for one hour, then at 0° C. for 1.5hours. The reaction mixture was treated with glacial HOAc (8 ml), thenquenched with 50% saturated NH₄ Cl and extracted with EtOAc. The aqueouslayer was back-extracted with EtOAc. The organic layers were combinedand washed with H₂ O and brine, then dried over Na₂ SO₄, filtered andconcentrated to afford a dark oily residue. The residue was dried underhigh vacuum and used in the next step without further purification.

B.1-(4-Fluorophenyl)-9,10-dihydro-3-(1-methylethyl)-2-phenanthrenecarboxylicacid, ethyl ester

A mixture of crude 1,5 diketone A, ammonium acetate (6.47 gm, 84.0 mmol)and copper (II) acetate (13.97 gm, 70.0 mmol) in glacial acetic acid (75ml) was allowed to reflux for 16 hours. The reaction mixture was thencooled and poured into an ice cold mixture of NH₄ OH/H₂ O (120 ml/150ml). The mixture was extracted with ether (twice) and the ether extractswere washed with water (twice) and brine, then dried over MgSO₄,filtered and concentrated. The dark oily residue was purified by flashchromatography (10% ether/hexane) to afford compound B as a pink solid(5.2 gm, 46% from the naphthalenone), which was contaminated with ahigher Rf component.

TLC: Rf 0.5 (10% ether/hexane), UV+Rf 0.62 (10% ether/hexane), UV,fluorescence

C.1-(4-Fluorophenyl)-9,10-dihydro-3-(1-methylethyl)-2-phenanthrenemethanol

A 0° C. solution of ester B in dry THF (60 ml) was treated with LAH(1.46 gm, 38.52 mmol). Ten minutes after the addition the solution waswarmed to room temperature and stirred for two hours. The reactionmixture was then cooled to 0° C. and quenched by dropwise addition of1.46 ml of H₂ O in THF (10 ml), then 1.46 ml 15% NaOH, and finally 3.0ml H₂ O. The precipitated aluminum salts were filtered out of solutionand washed with EtOAc and ether. The filtrate and washings were combinedand washed with water and brine, then dried over Na₂ SO₄, filtered andconcentrated to give an oily residue. Purification by flashchromatography (Merck silica gel, 10% ether/hexane, followed by 10%EtOAc/hexane) afforded a colorless oil which solidified on standingunder high vacuum. Recrystallization of the solid from hexane affordedcompound C as a white solid (4.0 gm, 89.8%).

m.p. 138°-139° C. Rf 0.42 (20% EtOAc/hexane), UV Analysis for C₂₃ H₂₂NFO*0.18 H₂ O: Calc'd: C 78,79 H 6.43 N 4.00 F 5.42 Found: C 78.80 H6.45 N 3.99 F 5.24

D.1-(4-Fluorophenyl)-9,10-dihydro-3-(1-methylethyl)-2-phenanthrenecarboxaldehyde

A solution of NMO (0.989 gm, 8.44 mmol) in CH₂ Cl₂ (30 ml) was allowedto stir over MgSO₄ for 30 minutes before being added to a mixture ofcompound C (1.647 gm, 4.56 mmol) and 4 angstrom sieves (2.67 gm) in CH₂Cl₂ (20 ml). The mixture was allowed to stir 5 minutes at roomtemperature, then TPAP (0.087 gm, 0.25 mmol) was added to the flask andthe solution stirred for an additional hour. The mixture was dilutedwith ether, then filtered through a Celite® pad and washed with etherand EtOAc. The filtrate and washings were combined and concentrated to adark green solid. The solid was purified by flash chromatography onMerck silcia gel in 15% EtOAc in hexane. The desired fractions werecombined and concentrated to a white solid. The white solid wasrecrystallized from hexane to afford compound D as hard white crystals(1.364 gm, 83%).

m.p. 129°-130° C. TLC: Rf 0.62 (25% EtOAc in hexane)

E.2-(2,2-Dibromoethenyl)-1-(4-fluorophenyl)-3-(1-methylethyl)phenanthrene

A solution of CBr₄ (0.281 gm, 0.836 mmol) in CH₂ Cl₂ (5 ml) was addeddropwise to a 0° C. solution of aldehyde D (0.200 gm, 0.557 mmol) andtriphenylphosphine (0.470 gm, 1.78 mmol) in CH₂ Cl₂ (20 ml). Thesolution was allowed to stir 30 minutes at 0° C., then warmed to roomtemperature over 15 minutes. The solution was then quenched with NaHCO₃and diluted with EtOAc and ether. The organic layer was washed withbrine, then dried over Na₂ SO₄, filtered and concentrated to a yellowsolid. The solid was purified by flash chromatography on Merck silicagel in 15% EtOAc in hexane. The desired fractions were combined andconcentrated to a white solid. The solid was recrystallized from hexaneto afford compound E as large clear crystals (0.254 gm, 88.5%).

m.p. 121°-122° C. Elemental Analysis dor C₂₄ H₂₀ NBr₂ F*0.18 H₂ O:Calc'd: C 57.14 H 4.07 N 2.78 Br 31.68 F 3.77 Found: C 57.53 H 3.92 N2.72 Br 31.21 F 3.83

F.(S)-4-[[[4-(4-Fluorophenyl)-5,6-dihydro-2-(1-methylethyl)benzo[h]quinolin-3-yl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

N-BuLi (2.5M in hexane, 1.31 ml, 3.27 mmol) was added dropwise to asolution of vinyl dibromide E (0.780 gm, 1.56 mmol) in THF (10 ml) at-78° C. under argon. The solution was allowed to stir 1 hour at -78° C.,then cannulated into a THF solution (15 ml) of the chloridate fromExample 57, part G, which had also been cooled to -78° C. The solutionwas stirred 30 minutes at -78° C., then quenched with saturated NH₄ Cland warmed to 0° C., and then saturated NaHCO₃ was added. The solutionwas diluted with ether and the organic layer was washed with brine, thendried over Na₂ SO₄, filtered and concentrated to a dark orange oil. Theoil was purified by flash chromatography on Merck silica gel in 45%EtOAc in hexane. The desired fractions were combined and concentrated toafford compound F as a brown oil (0.385 gm, 33%).

TLC: Rf 0.62 (1:1, EtOAc:hexane)

G.(S)-4-[[[4-(4-Fluorophenyl)-5,6-dihydro-2-(1-methylethyl)benzo[h]quinolin-3-yl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

(Bu)₄ NF (1M in THF, 1.55 ml, 1.55 mmol) was added to a solution ofcompound F (0.385 gm, 0.52 mmol) and HOAc (0.125 gm, 2.08 mmol) in THF(10 ml) under argon and allowed to stir 17 hours at room temperature.The reaction mixture was diluted with EtOAc, then washed with 5% KHSO₄(three times). The aqueous layers were back-extracted with EtOAc(twice). The organic layers were pooled and washed with brine, thendried over Na₂ SO₄, filtered and concentrated to afford an orange oil.The oil was dissolved in ether (10 ml) and treated with excess CH₂ N₂.Excess CH₂ N₂ was removed with a stream of argon, and the solution wasconcentrated to give an orange oil. The oil was purified by flashchromatography on Merck silica gel in 35% acetone in hexane. The desiredfractions were pooled and concentrated to afford compound G as a clearoil (0.195 gm, 70%).

TLC: Rf 0.80 (8:1:1, CH₂ Cl₂ :MeOH:HOAc)

H.(S)-4-[[[4-(4-Fluorophenyl)-5,6-dihydro-2-(1-methylethyl)benzo[h]quinolin-3-yl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A solution of compound G (0.190 gm, 0.357 mmol) in dioxane (10 ml) wastreated with NaOH (1M in H₂ O, 1.10 ml 1.10 mmol), then heated to 55° C.and allowed to stir 3 hours. The solution was cooled to room temperatureand concentrated to a white solid. The solid was dissolved in water andchromatographed on HP-20 resin, eluting first with water (200 ml), thenwith 50% MeOH in water (400 ml), and finally with MeOH (200 ml). Thedesired fractions were pooled and concentrated. The resultant whitesolid was dissolved in water and lyophilized to give Example 86 as afluffy white solid (0.150 gm, 76%).

m.p. 282° C. (decomp) Elemental Analysis for C₂₈ H₂₅ FNO₅ P*2 Na*2.25 H₂O: Calc'd: C 56.81 H 5.02 N 2.37 F 3.21 P 5.23 Found: C 56.84 H 4.83 N2.48 F 3.44 P 4.84 Optical Rotation: [a]_(D) =+11.4° (MeOH, C=4.0 mg/ml)

Example 87(S,E)-4-[[2-[5-Ethyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A.5-Ethyl-3-ethynyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridine

To a solution of compound E from Example 59 (2.001 gm, 4.0 mmol) in dryTHF (15 ml) at -78° C. was added n-BuLi (2.5M in hexanes, 3.80 ml, 9.5mmol) over a 1-minute period. After stirring at -78° C. for 50 minutes,the clear green solution was quenched with saturated NH₄ Cl and warmedto room temperature. The mixture was diluted with H₂ O, Et₂ O, and EtOAcand the mixture was shaken in a separatory funnel. The organic layercontained a finely divided white solid. The organic layer was washedwith brine and filtered to give approximately 1 gram of solid.Additional solid was obtained after evaporation of the organic filtrate.The pooled solids were refluxed in EtOAc/acetone, diluted with hexane,and cooled to give the acetylene title compound (1.253 gm, 91%) as awhite solid that is poorly soluble in most common organic solvents.

m.p. 245° C. TLC R_(f) 0.44 (10% EtOAc in hexane) Analysis for C₂₄ H₂₂FN: Calc'd: C 83.93 H 6.46 N 4.08 F 5.53 Found: C 83.53 H 6.28 N 4.06 F5.68

B.5-Ethyl-4-(4-fluorophenyl)-3-(2-iodoethynyl)-2-(1-methylethyl)-6-phenylpyridine

A mixture of compound A (1.222 gm, 3.56 mmol) and AIBN (20 mg) intri-n-butylstannyl hydride (2.3 ml) was rapidly heated to 140° C. byimmersion in a pre-heated oil bath. Approximately 20 mg of AIBN wasadded to the reaction mixture one and two hours after heating wasinitiated. After 3 hours, the mixture was cooled to room temperature,diluted with Et₂ O (40 ml) and treated with solid I₂ (3.40 gm, 13.4mmol). The dark reaction mixture was stirred for 50 minutes, then pouredinto a 50% saturated NaHCO₃ solution containing 6.8 gm Na₂ S₂ O₃. Thelayers were shaken and separated. The ethereal layer was washedsuccessively H₂ O, 1.7M NH₄ OH, H₂ O, and brine, then dried (Na₂ SO₄),filtered and stripped to yield an oil. The residue was subjected toflash chromatography (Merck SiO₂, 10% EtOAc in hexane) to afford thecrude title compound as a solid. Recrystallization from hexane gave thetitle compound (1.389 gm, 87%) as pale yellow crystals.

m.p. 116.8°-118.8° C. TLC R_(f) 0.36 (4% EtOAC in hexane) Microanalysisfor C₂₄ H₂₃ FNI: Calc'd: C 61.15 H 4.92 N 2.97 F 4.03 I 26.92 Found: C60.34 H 4.92 N 2.69 F NA I 26.53

C.(S,E)-4-[[2-[5-Ethyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

A solution of the part B vinyl iodide (1.300 gm, 2.76 mol) in THF (8 ml)was added over a 5-minute period to a -100° C. solution oft-butyllithium (1.7M in pentane, 3.40 ml, 5.8 mmol) in THF (8 ml). Theresulting solution was stirred for 15 minutes, then added over a10-minute period to a -100° C. solution of the phosphonochloridate fromExample 57, part G in THF (15 ml). The resulting yellow mixture wasstirred at minus 100° C. for 10 minutes, then at -78° C. for 30 minutes,then quenched with 50% saturated NH₄ Cl. The solution was warmed to roomtemperature, diluted with H₂ O, and poured into saturated NaHCO₃. Theaqueous phase was extracted with Et₂ O. The Et₂ O extract was washedwith brine, dried (Na₂ SO₄), filtered and stripped. The resultingyellow-orange oil was chromatographed (flash, LPS-1, 50% EtOAc inhexane) to afford the title compound as a tan foam (1.261 gm, 59%).

TLC R_(f) 0.21 (40% EtOAc in hexane)

D.(S,E)-4-[[2-[5-Ethyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

A solution of the part C compound (1.241 gm, 1.59 mmol) in THF (15 ml)was treated with HOAc (470 ul, 493 mg, 8.2 mmol) andtetra-n-butyl-ammonium fluoride (1.0M in THF, 7.8 ml, 7.8 mmol). Afterstirring at room temperature for 16 hours, the solution was poured intosaturated NaHCO₃ and extracted with EtOAc. The EtOAc extract was washedwith brine, dried (Na₂ SO₄), filtered, and stripped to give an oil,which was subsequently chromatographed (flash, Merck SiO₂, 40% acetonein hexane followed by 60% acetone in hexane). Compound D (770 mg, 90%)was obtained as a white foam.

TLC R_(f) 0.40 (1:1 acetone:hexane)

E.(S,E)-4-[[2-[5-Ethyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A solution of compound D (286 mg, 0.53 mmol) in dioxane (3 ml) wastreated with 1N NaOH (1.9 ml, 1.9 mmol) and the mixture was stirred at60° C. for 1 hour. The solvent was evaporated and the residue was takenup in H₂ O and chromatographed on HP-20, eluting in succession with H₂ O(150 ml) and 50% MeOH in H₂ O (200 ml). The desired fractions werepooled and evaporated and the residue was taken up in H₂ O andlyophilized to give Example 87 (270 mg, 82%) as a white solid.

m.p. 285° C. (decomp.); [a]_(D) =+10.9° (MeOH, c=0.52) TLC R_(f) 0.12(8:1:1--CH₂ Cl₂ :HOAc:MeOH) Microanalysis for C₂₈ H₂₉ FNNa₂ O₅ P×3.85 H₂O: Calc'd: C 53,83 H 5.92 N 2.24 F 3.04 P 4.96 Found: C 53.87 H 5.65 N2.19 F 3.11 P 4.95

Example 88(S)-4-[[2-[5-Ethyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A.(S)-4-[[2-[5-Ethyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

A mixture of compound C from Example 87 (467 mg, 0.865 mmol) and Pd oncarbon (10% Pd on C, 100 mg) in MeOH (20 ml) was shaken under 50 psi ofH₂ for 3 days. The solution was filtered, stripped, and chromatographed(flash, Merck SiO₂, 50% acetone in hexane) to give compound A (411 mg,88%) as a colorless oil.

TLC R_(f) 0.39 (1:1--acetone:hexane)

B.(S)-4-[[2-[5-Ethyl-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A solution of compound A (393 mg, 0.725 mmol) in dioxane (5 ml) wastreated with 1N NaOH (2.5 ml, 2.5 mmol) and the mixture was stirred at60° C. for 2 hours. The solvent was evaporated and the residue waschromatographed on HP-20, eluting in succession with H₂ O (150 ml) and50% MeOH in H₂ O (200 ml). The desired fractions were pooled andevaporated and the residue was taken up in H₂ O and lyophilized to giveExample 88 (346 mg, 77%) as a white solid.

m.p. 297° C. (decomp.); [a]_(D) =+1.0° (MeOH, c=0.48) TLC R_(f) 0.11(8:1:1--CH₂ Cl₂ :HOAc:MeOH) Microanalysis for C₂₈ H₃₁ FNNa₂ O₅ P×3.33 H₂O: Calc'd: C 54.46 H 6.15 N 2.27 F 3.08 P 5.02 Found: C 54.46 H 5.87 N2.26 F 3.05 P 4.93

Example 89(S)-4-[[[4-(4-Fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A. 4-Fluoro-2-methylbenzaldehyde

n-BuLi (2.6M in hexane, 57 ml, 143 mmol) was added over 15 minutes to aTHF solution (200 ml) of 2-methyl-4-fluorophenylbromide, cooled to -78°C. and allowed to stir 1 hour at -78° C. DMF (26.61 gm, 364 mmol) wasthen added over 2 minutes, and the solution was allowed to stir anotherhour. The reaction was quenched with NH₄ Cl and warmed to roomtemperature. 10% HCl was added until the solution became acidic. Themixture was diluted with ether and the organic layer washed with waterand brine, then dried over MgSO₄, filtered and concentrated to give anorange oil. The oil was purified by distillation (bp=69° C. at 7 mm Hg)to afford aldehyde A as a clear liquid (13.284 gm, 74%).

TLC: Rf 0.30 (10% EtOAc in hexane)

B. 3-(4-Fluoro-2-methylphenyl)-1-phenyl-2-propen-1-one

A solution of sodium ethoxide in ethanol (21% by weight, 3.08 gm, 9.50mmol) was added to a mixture of aldehyde A (13.084 gm, 95 mmol) andacetophenone (11.38 gm, 95 mmol, from Aldrich) in ethanol (125 ml).After stirring at room temperature for 17 hours, the solution wasconcentrated to about 30 ml to give an orange oil. The oil was dissolvedin ether and EtOAc, washed with water and brine, then dried over MgSO₄,filtered and concentrated to afford an orange oil. The oil was purifiedby flash chromatography on Merck silica gel in 5-10% EtOAc in hexane.Fractions containing product B, were pooled and concentrated to affordcompound B as a pale yellow oil (17.285 gm, 76%).

TLC: Rf 0.39 (10% EtOAc in hexane)

C.β-(4-Fluoro-2-methylphenyl)-α-(2-methyl-1-oxopropyl)-Δ-oxobenzenepentanoicacid, ethyl ester

A solution of sodium ethoxide in ethanol (21% by weight, 3.49 gm, 10.8mmol) was added to a mixture of enone B (17.280 gm, 72 mmol) andethylisobutyrylacetate (17.086 gm, 108 mmol) in ethanol (300 ml) andstirred at room temperature for 6 hours, the solution was concentratedto about 50 ml, dissolved in ether and EtOAc, washed with saturated NH₄Cl, water and brine, then dried over MgSO₄, filtered and concentrated toafford an orange oil. The oil was purified by flash chromatography onMerck silica gel in 5-10% EtOAc in hexane. Fractions containing theproduct were pooled and concentrated to give compound C as a white,crystalline solid (23.905 gm, 87%).

m.p.=73°-77° C. TLC: Rf 0.38, 0.43 (15% EtOAc in hexane)

D.4-(4-Fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxylicacid, ethyl ester

NH₄ OAc (14.47 gm, 188 mmol) and Cu(OAc)₂ (31.23 gm, 156 mmol) wereadded to an acetic acid solution (100 ml) of 1,5 diketone C (23.905 gm,62.6 mmol). The resulting mixture was allowed to reflux for 13 hourswhile stirring under argon. The solution was then poured into anice-cold solution of NH₄ OH/H₂ O (125 ml/150 ml). The mixture wasextracted with EtOAc (twice), washed with water and saturated NaCl, thendried over MgSO₄, filtered and concentrated to afford an orange oil. Theoil was purified by flash chromatography on Merck silica in 5% EtOAc inhexane. Those fractions containing pure product D were pooled andconcentrated to give a clear oil (19.140 gm, 81%).

TLC: Rf 0.63 (10% EtOAc in hexane)

E.4-(4-Fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinemethanol

A THF solution (20 ml) of ester D (19.140 gm, 50.8 mmol) was cooled to0° C. and treated with LiAlH₄ (5.78 gm, 152 mmol). After stirring 15minutes at 0° C., the solution was warmed to room temperature andstirred for an additional 3 hours. The solution was cooled to 0° C. andquenched by dropwise addition of 5.8 ml of water followed by 5.8 ml of15% NaOH, then 17.0 ml water. The aluminum paste was filtered out ofsolution and the filtrate concentrated to a white solid.Recrystallization of the solid from EtOAc/hexane gave compound E ashard, white crystals (15.072 gm, 94%).

m.p. 134°-135° C. TLC: Rf 0.62 (27% EtOAc in hexane) Elemental Analysisfor C₂₂ H₂₂ NFO: Calc'd C, 78.78; H, 6.61; N, 4.18; F, 5.66 Found C,78.85; H, 6.68; N, 4.18; F, 5.54

F.4-(4-Fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde

DMSO (9.66 gm, 124 mmol) was added to a -78° C. solution of oxalylchloride (7.85 gm, 61.9 mmol) in methylene chloride (200 ml). Themixture was allowed to stir 20 minutes at -78° C. under argon. CompoundE (15.072 gm, 47.5 mmol) was then added dropwise to the flask as amethylene chloride (50 ml) solution. Twenty minutes later, triethylamine (33 ml, 0.327 mmol) was added dropwise to the cloudy whitesolution, and the mixture was stirred for 20 minutes, then warmed toroom temperature. The solution was diluted with ether and the organiclayer washed with water and brine, then dried over Na₂ SO₄, filtered andconcentrated to afford a yellow oil. The compound was purified by flashchromatography on Merck silica gel in 10% EtOAc in hexane. The desiredfractions were combined and concentrated to afford product F as ayellow, crystalline solid (13.70 gm, 92%).

m.p. 90°-93° C. TLC: Rf 0.62 (15% EtOAc in hexane) Elemental Analysisfor C₂₂ H₂₀ NFO: Calc'd C, 79.26; H, 6.05; N, 4.20; F, 5.70 Found C,79.27; H, 6.06; N, 4.20; F, 5.82

G.3-(2,2-Dibromoethenyl)-4-(4-fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenylpyridine

A solution of CBr₄ (21.95 gm, 65.2 mmol) in methylene chloride (75 ml)was added over 20 minutes to a 0° C. solution of aldehyde F (13.70 gm,43.5 mmol) and triphenyl phosphine (36.51 gm, 139 mmol) in methylenechloride (250 ml). The solution stirred at 0° C. for an additional 30minutes, then warmed to room temperature over 40 minutes. SaturatedNaHCO₃ was then added to quench the reaction. The organic layer waswashed with brine, then dried over Na₂ SO₄, filtered and concentrated toabout 100 ml. The solution was purified by flash chromatography on Mercksilica gel in 15% EtOAc in hexane. The desired fractions were pooled andconcentrated to afford a yellowish solid. The solid was recrystallizedfrom hexane to afford product G as hard, clear crystals (16.560 gm,81%).

m.p. 128°-129° C. TLC: Rf 0.37 (5% EtOAc in hexane) Elemental Analysisfor C₂₃ H₂₀ NBr₂ F: Calc'd C, 56.47; H, 4.12; N, 2.86; Br, 32.67; F,3.88 Found C, 56.71; H, 4.00; N, 2.82; Br, 32.46; F, 3.86

H.3-Ethynyl-4-(4-fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenylpyridine

A solution of vinyl dibromide G (8.280 gm, 17.6 mmol) in THF (10 ml) wasadded dropwise to a solution of n-BuLi (2.5M in hexane, 14.7 ml, 36.9mmol) in THF (20 ml) stirring at -78° C. under argon. The solution wasallowed to stir 1 hour at -78° C., then quenched with saturated NH₄ Cland warmed to 0° C., then saturated NaHCO₃ was added to the solution.The mixture was diluted with ether, and the organic layer was washedwith brine, dried over Na₂ SO₄, filtered and concentrated to give yellowoil. The oil was purified by flash chromatography on Merck silica gel in1% EtOAc in hexane. The desired fractions were combined and concentratedto afford compound H as a white solid (5.514 gm, 95%).

m.p. 72°-74° C. TLC: Rf 0.32 (1% EtOAc in hexane) Elemental Analysis forC₂₃ H₂₀ NF: Calc'd C, 83.86; H, 6.12; N, 4.25; F, 5.77 Found C, 83.72;H, 6.02; N, 4.21; F, 5.68

I.(S)-4-[[[4-(4-Fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

n-BuLi (2.5M in hexane, 0.67 ml, 1.67 mmol) was added dropwise to asolution of acetylene H (0.500 gm, 1.52 mmol) in THF (10 ml) at -78° C.under argon. The solution was allowed to stir 1 hour at -78° C., thencannulated into a THF solution (15 ml) of the chloridate from Example57, part G, which had also been cooled to -78° C. The solution wasstirred 30 minutes at -78° C., then quenched with saturated NH₄ Cl andwarmed to 0° C., then saturated NaHCO₃ was added to the solution. Thesolution was diluted with ether and the organic layer was washed withbrine, then dried over Na₂ SO₄, filtered and concentrated to a darkorange oil. The oil was purified by flash chromatography on Merck silicagel in 45% EtOAc in hexane. The desired fractions were combined andconcentrated to afford compound I as a beige foam (0.878 gm, 76%).

TLC: Rf 0.47 (40% EtOAc in hexane)

J.(S)-4-[[[4-(4-Fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

(Bu)₄ NF (1M in THF, 3.86 ml, 3.86 mmol) was added to a solution ofsilyl ether I (0.878 gm, 1.28 mmol) and HOAc (0.307 gm, 5.12 mmol) inTHF (20 ml) under argon and allowed to stir 16 hours at roomtemperature. The reaction mixture was diluted with EtOAc, then washedwith 5% KHSO₄ (3 times). The aqueous layers were back-extracted withEtOAc (twice). The organic layers were pooled and washed with brine,then dried over Na₂ SO₄, filtered and concentrated to afford a brownoil. The oil was dissolved in ether (15 ml) and treated with excess CH₂N₂. Excess CH₂ N₂ was removed with a stream of argon, and the solutionwas concentrated to give a brown-yellow oil. The oil was purified byflash chromatography on Merck silica gel in 50% acetone in hexane. Thedesired fractions were pooled and concentrated to afford compound J as aclear oil (0.325 gm, 48%).

TLC: Rf 0.63 (50% acetone in hexane)

K.(S)-4-[[[4-(4-Fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A solution of compound J (0.325 gm, 0.62 mmol) in dioxane (10 ml) wastreated with NaOH (1M in H₂ O, 2.20 ml, 2.20 mmol), then heated to 55°C. and allowed to stir 2 hours. The solution was then cooled to roomtemperature and concentrated to a white solid. The solid was dissolvedin water and chromatographed on HP-20 resin, eluting first with water(200 ml), then with 50% MeOH in water (400 ml), and finally with MeOH(200 ml). The desired fractions were pooled and concentrated. Theresultant white solid was dissolved in water and lyophilized to giveExample 89 as a fluffy white solid (0.300 gm, 90%).

m.p. 305° C. (decomp). TLC: Rf 0.64 (6:3:1, n-propanol:NH₄ OH;H₂ O)Elemental Analysis for C₂₇ H₂₅ NFNa₂ PO_(5x) 3.0 H₂ O: Calc'd C, 56.41;H, 5.06; N, 2.27; F, 3.08; P, 5.02 Found C, 56.37; H, 4.89; N, 2.30; F,3.12; P, 5.36 Optical Rotation: [a]_(D) =+8.8° (MeOH, c=3.8 mg/ml)

Example 90(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A. 3-Cyclopropyl-3-oxopropanoic acid, ethyl ester

To a slurry of NaH (60% in mineral oil, 19.200 gm, 0.48 mol) in drydiethyl carbonate (80 ml) was added a solution of methyl cyclopropylketone (23.5 ml, 20.00 gm, 0.238 mol) in Et₂ O (30 ml). After theaddition of approximately 10% of the ketone solution, EtOH (0.25 ml) wasadded and addition of the ketone continued. Soon after the addition wascomplete, the reaction became quite exothermic with vigorous H₂evolution. Periodic cooling with an ice bath was required. After onehour, H₂ evolution had ceased and the mixture was diluted with Et₂ O(200 ml) and hexane (185 ml). The solution was cooled in an ice bath andcarefully treated with 5% HCl (10 ml), at which time a thick slurrydeveloped. The solid was collected by filtration and washed with hexane.The solid was then partitioned between Et₂ O and 5% HCl until all of thesolid had dissolved and the aqueous layer remained acidic. The organiclayer was separated and washed with H₂ O, saturated NaHCO₃, and brine,then dried (MgSO₄), filtered and stripped. The liquid residue wassubjected to flash chromatography (Merck SiO₂, 20% EtOAc in hexane) toprovide compound A (20.357 gm, 55%) as a yellow liquid.

TLC R_(f) 0.24 (20% EtOAc in hexane)

B. 3-Fluorophenyl-1-phenyl-2-propen-1-one

A solution of benzaldehyde (19.220 gm, 181 mmol) andp-fluoroacetophenone (25.000 gm, 181 mmol) in ethanol (200 ml) wastreated with sodium methoxide (1.972 gm, 36.5 mmol). A precipitate fellout of solution after 30 minutes. After stirring at room temperature for15 hours, the solution was treated with 50 ml of H₂ O, cooled in an icebath, and filtered. The solid was rinsed with cold ethanol and driedunder high vacuum to yield compound B (29.730 gm, 73%) as a yellowcrystalline solid.

m.p. 76.3°-77.5° C. TLC R_(f) 0.46 (20% EtOAc in hexane) Microanalysisfor C₁₅ H₁₁ FO: Calc'd C, 79.63; H, 4.90; F, 8.40 Found C, 79.57; H,4.77; F, 8.30

C. α-(2-Cyclopropyl-1-oxoethyl)-β-(4-fluorophenyl)-Δ-oxophenylpentanoicacid, ethyl ester

A mixture of compound B (7.280 gm, 32.2 mmol) and compound A (6.00 gm,38.4 mmol) in absolute EtOH (100 ml) was treated with a solution ofEtONa in EtOH (21% by weight solution, 1.28 gm, 4.8 mmol). Afterstirring at room temperature for 30 minutes, a thick precipitate fellout of solution. Additional EtOH (40 ml) was added and stirringcontinued for an hour. The solution was treated with acetic acid (0.28ml) and cooled to 0° C. The solid was collected by filtration, washedwith cold EtOH and hexane, and dried in vacuo to give compound C, amixture of diastereomers, as a white amorphous solid (10.295 gm, 84%).

m.p. 114°-117° C. TLC R_(f) 0.21 (20% EtOAc in hexane)

D. 2-Cyclopropyl-4-(4-fluorophenyl)-6-phenyl-3-pyridinecarboxylic acid,ethyl ester

A mixture of compound C (10.113 gm, 26.4 mmol), NH₄ OAc (6.142 gm, 79.7mmol), and Cu(OAc)₂ (13.920 gm, 70.0 mmol) in glacial HOAc (70 ml) washeated at 110° C. for 0.5 hours. Additional NH₄ OAc (2.10 gm) was addedand heating continued for four more hours. The solution was cooled toroom temperature and subsequently poured into an ice cold mixture ofconcentrated NH₄ OH (85 ml) in H₂ O (150 ml). The mixture was extractedwith Et₂ O and the Et₂ O extract was washed with H₂ O (twice) and brine,then dried (Na₂ SO₄), filtered and stripped to yield a yellow oil thatsolidified on standing. Recrystallization from EtOAc/hexane affordedcompound D as a pale yellow solid (7.810 gm). The mother liquor wasflashed (Merck SiO₂, 10% EtOAc in hexane) to give additional product,which was recrystallized from hexane (477 mg). Total pooled solids were8.287 gm, 87 % yield.

m.p. 89.5°-92° C. TLC R_(f) 0.50 (20% EtOAc in hexane) Microanalysis forC₂₃ H₂₀ FNO₂ : Calc'd C, 76.43; H, 5.58; N, 3.88; F, 5.26 Found C,76.40; H, 5.58; N, 3.70; F, 5.15

E. 2-Cyclopropyl-4-(4-fluorophenyl)-6-phenyl-3-pyridinemethanol

A cold (0° C.) solution of ester D (7.798 gm, 21.6 mmol) in dry THF (200ml) was treated with LiAlH₄ (2.378 gm, 62.7 mmol). Ten minutes after theaddition, the cooling bath was removed and the mixture was stirred atroom temperature for one hour. The solution was recooled to 0° C. andquenched in succession with H₂ O (2.5 ml), 10% NaOH (4.0 ml), and H₂ O(7.5 ml). The solution was filtered and the salts were washed with EtOAcand Et₂ O. Removal of the filtrate solvent afforded a solid. The solidwas recrystallized from EtOAc/hexane to provide compound E (5.866 gm,85%) as an amorphous white solid.

m.p. 176°-177° C. TLC R_(f) 0.53 (40% EtOAc in hexane) Microanalysis forC₂₁ H₁₈ FNO: Calc'd C, 78.97; H, 5.68; N, 4.39; F, 5.95 Found C, 78.72;H, 5.67; N, 4.23; F, 5.67

F. 2-Cyclopropyl-4-(4-fluorophenyl)-6-phenyl-3-pyridinecarboxaldehyde

A solution of 4-methylmorpholine-N-oxide (2.982 gm, 25.5 mmol) in CH₂Cl₂ (80 ml) was dried over MgSO₄ for 15 minutes. The solution wasfiltered directly into a 500 ml flask, using approximately 20 ml CH₂ Cl₂to effect the transfer. The flask was then charged with dry 4 angstrommolecular sieves (10.4 gm), alcohol E (4.012 gm, 12.56 mmol), andtetrapropylammonium perruthenate (222 mg, 0.63 mmol). After stirring atroom temperature for 40 minutes, the black solution was diluted with Et₂O (120 ml), stirred for 5 minutes, then filtered through Celite®. Thefiltrate was stripped and the dark residue was dissolved in CH₂ Cl₂ andflashed (Merck SiO₂, 20% EtOAc in hexane) to give the product as asolid. The solid was recrystallized from EtOAc/hexane (2 crops) to givecompound F (3.115 gm, 78%) as a yellow solid.

m.p. 110°-113° C. TLC R_(f) 0.52 (20% EtOAc in hexane)

G.3-(2,2-Dibromoethenyl)-2-cyclopropyl-4-(4-fluorophenyl)-6-phenylpyridine

A solution of carbon tetrabromide (4.245 gm, 12.8 mmol) in CH₂ Cl₂ (10ml) was added over a 9-minute period to a cold (0° C.) solution ofaldehyde F (2.725 gm, 8.6 mmol) and triphenylphosphine (6.761 gm, 25.8mmol) in CH₂ Cl₂ (35 ml). After the addition was complete, the coolingbath was removed and the mixture was stirred at room temperature for 25minutes. The solution was quenched with saturated NaHCO₃ and extractedtwice with CH₂ Cl₂. The combined organic layers were dried (Na₂ SO₄),filtered and concentrated. The concentrate was chromatographed (flash,Merck SiO₂, 35% CH₂ Cl₂ in hexane) to give impure dibromide G as asolid. Recrystallization from EtOAc/hexane (2 crops) provided compound G(3.588 gm, 88%) as fine white needles.

m.p. 170°-172° C. TLC R_(f) 0.58 (20% EtOAc in hexane) Microanalysis forC₂₂ H₁₆ Br₂ FN: Calc'd C, 55.84; H, 3.41; N, 2.96; F, 4.02; Br, 33.77Found C, 55.95; H, 3.20; N, 2.77; F, 4.21; Br, 33.59

H.(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

A solution of dibromide G (1.000 gm, 2.11 mmol) in THF (7 ml) was addeddropwise to a solution of n-BuLi (2.5M in hexane, 1.8 ml, 4.5 mmol) inTHF (10 ml) at -78° C. over a 6-minute period. The resulting clearyellow solution was stirred at -78° C. for 40 minutes, then addeddropwise via cannula over a 10-minute period to a -78° C. solution ofthe phosphonochloridate from Example 57, part G in THF (15 ml). Theresulting greenish mixture was stirred at -78° C. for 20 minutes, thenquenched with 50% saturated NH₄ Cl. The solution was warmed to 0° C.,diluted with H₂ O, and poured into saturated NaHCO₃. The aqueous phasewas extracted once with Et₂ O. The Et₂ O layer was washed with brine,dried (Na₂ SO₄), filtered and stripped to give a yellow oil. The residuewas chromatographed (flash, Merck SiO₂, 40% EtOAc in hexane) to affordcompound H as a white foam (1.270 gm, 81%).

TLC R_(f) 0.25 (40% EtOAc in hexane)

I.(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

A mixture of compound H (1.255 gm, 1.68 mmol) and HOAc (490 μl, 514 mg,8.6 mmol) in THF (25 ml) was treated with tetra-n-butylammonium fluoride(1.0M in THF, 8.2 ml, 8.2 mmol). After stirring at room temperature for16 hours, the solution was diluted with EtOAc and washed 3 times with 5%KHSO₄. The EtOAc layer was washed with brine, dried (Na₂ SO₄), filteredand stripped to afford a yellow oil. The oil was dissolved in Et₂ O,cooled to 0° C. and treated with excess diazomethane for 15 minutes. Theexcess diazomethane was destroyed by the addition of HOAc and thesolvent was removed in vacuo. The residue was chromatographed (flash,Merck SiO₂, 1:1--acetone:hexane) to afford compound I (746 mg, 87%) as awhite foam.

TLC R_(f) 0.30 (1:1--acetone:hexane)

J.(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A solution of compound I (730 mg, 1.44 mmol) in dioxane (6 ml) wastreated with 1N NaOH (5.0 ml, 5.0 mmol) at room temperature and themixture was subsequently heated at 60° C. under argon for 0.5 hour. Thesolvent was evaporated and the residue was chromatographed on HP-20resin, eluting in succession with H₂ O (200 ml) and 50% MeOH in H₂ O(200 ml). The desired fractions were pooled and evaporated and theresidue was taken up in H₂ O and lyophilized to give Example 90 (674 mg,84%) as a white solid.

m.p. decomposition at 285° C. TLC R_(f) 0.07 (8:1:1--CH₂ Cl₂ :HOAc:MeOH)Analysis for C₂₆ H₂₁ FNNa₂ O₅ P×2.0 H₂ O: Calc'd C, 55.82; H, 4.51; N,2.50; F, 3.40; P, 5.54 Found: C, 55.84; H, 4.28; N, 2.46; F, 3.33; P,5.50 Rotation [a]_(D) =+5.6° (MeOH, 9.8 mg in 1.21 ml)

Example 91(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A. 3-Cyclopropyl-2-[(4-fluorophenyl)methylene]-3-oxopropanoic acid,ethyl ester

A mixture of 4-fluorobenzaldehyde (4.768 gm, 38.4 mmol), ethyl3-cyclopropyl-3-oxopropionate from Example 88, part A (6.000 gm, 38.4mmol), piperidine (380 μl), and HOAc (75 μl) was refluxed in benzene (40ml) with removal of water (Dean-Stark trap) for 16 hours. The cooledmixture was diluted with Et₂ O and washed successively with 5% HCl,saturated NaHCO₃, H₂ O, and brine, then dried (Na₂ SO₄), filtered, andstripped to yield an oil. Distillation of the oil (bp 127°-135° C. at0.2 mm Hg) afforded compound A (8.299 gm, 82%) as a pale yellow liquid.

TLC R_(f) 0.31 (20% EtOAc in hexane) Microanalysis for C₁₅ H₁₅ FO₃ :Calcd C, 68.69; H, 5.76; F, 7.24 Found C, 68.92; H, 5.90; F, 7.25

B.α-(1-Cyclopropyl-1-oxomethyl)-β-(4-fluorophenyl)-γ-methyl-Δ-oxophenylpentanoicacid, ethyl ester

A -78° C. solution of LiN(TMS)₂ (1.0M in THF, 38 ml, 38 mmol) in dry THF(40 ml) was treated with a solution of propiophenone (5.015 gm, 37.4mmol) in THF (6 ml) over a 4-minute period. After 30 minutes, a solutionof compound A (7.842 gm, 29.9 mmol) in THF (15 ml) was added dropwise tothe above solution. After one hour, the mixture was quenched with aceticacid (2.5 ml) and saturated NH₄ Cl and warmed to room temperature. Themixture was diluted with H₂ O and subsequently extracted once with Et₂O. The Et₂ O extract was washed with brine, dried (Na₂ SO₄), filtered,and stripped to give an oil. The oil was transferred to a round bottomflask which was fitted with a short path distillation apparatus and theoil was heated at 65° C. and 0.2 mm Hg to remove the volatiles andexcess propiophenone. The pot residue, crude compound B, was useddirectly in the next reaction.

C.2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinecarboxylicacid, ethyl ester

A mixture of crude compound B, NH₄ OAc (9.210 gm, 119.5 mmol), andCu(OAc)₂ (17.921 gm, 89.8 mmol) in glacial HOAc (80 ml) was heated at110° C. for 21 hours. The solution was cooled to room temperature andsubsequently poured into an ice cold mixture of concentrated NH₄ OH (100ml) in H₂ O (200 ml). The mixture was extracted twice with Et₂ O and thepooled Et₂ O extracts were washed with H₂ O and brine, then dried (Na₂SO₄), filtered and stripped to yield a brown solid. The solid wasdissolved in CH₂ Cl₂ and flashed (Merck SiO₂, 20% EtOAc in hexane) togive compound C as a reddish oil which readily solidified.Recrystallization from EtOAc/hexane (2 crops) afforded compound C (9.615gm, 86%) as white crystals.

m.p. 113°-114.5° C. TLC R_(f) 0.46 (20% EtOAc in hexane) Microanalysisfor C₂₄ H₂₂ FNO₂ : Calc'd C, 76.78; H, 5.91; N, 3.73; F, 5.06 Found C,76.68; H, 5.92; N, 3.63; F, 5.06

D. 2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinemethanol

A cold (0° C.) solution of ester C (8.942 gm, 23.8 mmol) in dry THF (200ml) was treated with LiAlH₄ (2.701 gm, 71.2 mmol). Ten minutes after theaddition, the cooling bath was removed and the mixture was stirred atroom temperature for 1.5 hours. The solution was recooled to 0° C. andquenched in succession with H₂ O (3.0 ml), 10% NaOH (4.5 ml), and H₂ O(8.5 ml). The solution was filtered and the salts were washed with EtOAcand Et₂ O. Removal of the filtrate solvent afforded an oily solidresidue. The residue was dissolved in Et₂ O, diluted with hexane, heatedto remove the Et₂ O, and cooled to provide compound D (6.548 gm, 83%) asan amorphous white solid.

m.p. 140.5°-142° C. TLC R_(f) 0.18 (20% EtOAc in hexane) Microanalysisfor C₂₂ H₂₀ FNO: Calc'd C 79.25 H 6.05 N 4.20 F 5.70 Found C 79.14 H5.99 N 4.15 F 5.73

E.2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinecarboxaldehyde

A solution of 4-methylmorpholine-N-oxide (4.002 gm, 34.2 mmol) in CH₂Cl₂ (130 ml) was dried over MgSO₄ for 15 minutes. The solution wasfiltered directly into a 500-ml flask, using approximately 30 ml CH₂ Cl₂to effect the transfer. The flask was then charged with dry 4 angstrommolecular sieves (16 gm), alcohol D (5.686 gm, 17.05 mmol), andtetrapropylammonium perruthenate (301 mg, 0.86 mmol). After stirring atroom temperature for 30 minutes, the black solution was diluted with Et₂O (200 ml), stirred for 5 minutes, then filtered through a plug ofsilica gel (Merck, 65×30 mm), washing with Et₂ O. The filtrate wasstripped to give a pale yellow solid. The solid was recrystallized fromEtOAc/hexane to give compound E (3.982 gm) as white crystals. Flashingthe mother liquor (Merck SiO₂, 20% EtOAc in hexane) gave additionalproduct, which was recrystallized from hexane (499 mg). Total pooledsolids were 4.481 gm (79%).

m.p. 137°-139° C. TLC R_(f) 0.50 (20% EtOAc in hexane) Microanalysis forC₂₂ H₁₈ FNO: Calc'd C, 79.74; H, 5.47; N, 4.23; F, 5.73 Found C, 79.32;H, 5.49; N, 4.13; F, 5.65

F.2-Cyclopropyl-3-(2,2-dibromoethenyl)-4-(4-fluorophenyl)-5-methyl-6-phenylpyridine

A solution of carbon tetrabromide (5.810 gm, 17.5 mmol) in CH₂ Cl₂ (9ml) was added over a 12-minute period to a cold (0° C.) solution ofaldehyde E (3.864 gm, 11.7 mmol) and triphenylphosphine (9.191 gm, 35.0mmol) in CH₂ Cl₂ (60 ml). After the addition was complete, the coolingbath was removed and the mixture was stirred at room temperature for 20minutes. The solution was quenched with saturated NaHCO₃ (40 ml) andextracted twice with CH₂ Cl₂. The combined organic layers were dried(Na₂ SO₄), filtered and concentrated. The concentrate waschromatographed (flash, Merck SiO₂, 40% CH₂ Cl₂ in hexane) and the puredesired fractions were stripped to give a solid. Recrystallization fromEtOAc/hexane (2 crops) provided compound F (5.432 gm, 96%) as whitecrystals.

m.p. 155°-157° C. TLC R_(f) 0.58 (20% EtOAc in hexane) Microanalysis forC₂₃ H₁₈ Br₂ FN: Calc'd C, 56.70; H, 3.72; N, 2.88; F, 3.90; Br, 32.80Found C, 56.55; H, 3.68; N, 2.82; F, 3.89; Br, 32.72

G.(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

A solution of dibromide F (1.000 gm, 2.05 mmol) in THF (5 ml) was addeddropwise to a solution of n-BuLi (2.5M in hexane, 1.73 ml, 4.3 mmol) inTHF (10 ml) at -78° C. over a 10-minute period. The resulting paleyellow solution was stirred at -78° C. for one hour, then added dropwisevia cannula over a 12-minute period to a -78° C. solution of thephosphonochloridate from Example 57, part G, in THF (15 ml). Theresulting mixture was stirred at -78° C. for 30 minutes, then quenchedwith 50% saturated NH₄ Cl. The solution was warmed to 0° C., dilutedwith H₂ O, and poured into saturated NaHCO₃. The aqueous phase wasextracted once with Et₂ O. The Et₂ O layer was washed with brine, dried(Na₂ SO₄), filtered and stripped to give an oil. The residue waschromatographed (flash, Merck SiO₂, 50% EtOAc in hexane) to affordcompound G as a white foam (1.158 gm, 74%).

TLC R_(f) 0.27 (40% EtOAc in hexane)

H.(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

A mixture of compound G (1.148 gm, 1.51 mmol) and HOAc (460 μl, 482 mg,8.0 mmol) in THF (25 ml) was treated with tetra-n-butylammonium fluoride(1.0M in THF, 7.6 ml, 7.6 mmol). After stirring at room temperature for17 hours, the solution was diluted with EtOAc and washed 3 times with 5%KHSO₄. The pooled aqueous extracts were back-extracted once with EtOAcand the combined EtOAc layers were washed with brine, dried (Na₂ SO₄),filtered and stripped to afford a yellow oil. The oil was dissolved inEt₂ O, cooled to 0° C. and treated with excess diazomethane for 15minutes. The excess diazomethane was destroyed by the addition of HOAcand the solvent was removed in vacuo. The residue was chromatographed(flash, Merck SiO₂, 40% acetone in hexane followed by 40% hexane inacetone) to afford compound H (684 mg, 87%) as a white foam.

TLC R_(f) 0.37 (1:1--acetone:hexane)

I.(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A solution of compound H (672 mg, 1.29 mmol) in dioxane (7 ml) wastreated with 1N NaOH (4.5 ml, 4.5 mmol) at room temperature and themixture was subsequently heated at 60° C. under argon for one hour. Thesolvent was evaporated and the solid residue was dissolved in warm H₂ Oand chromatographed on HP-20, eluting in succession with H₂ O (150 ml)and 50% MeOH in H₂ O (200 ml). The desired fractions were pooled andevaporated and the residue was taken up in H₂ O and lyophilized to giveExample 91 (640 mg, 89%) as a white solid.

m.p. decomposition at 295° C. TLC R_(f) 0.07 (8:1:1--CH₂ Cl₂ :HOAc:MeOH)Calc'd for C₂₇ H₂₃ FNNa₂ O₅ P×1.25 H₂ O: Calc'd C, 57.92; H, 4.59; N,2.50; F, 3.39; P, 5.53 Found C, 58.05; H, 4.50; N, 2.35; F, 3.38; P,5.72 Rotation [a]_(D) =+8.8° (MeOH, 7.6 mg in 1.22 ml)

Example 92(S)-4-[[2-[2-Ethyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A.(S)-4-[[2-[2-Ethyl-4-(4-fluorophenyl-5-methyl-6-phenyl-3-pyridinyl]ethyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

10% Pd/C (0.044 gm, 0.041 mmol) was added to a Parr bottle containing anargon-purged, MeOH (50 ml) solution of compound C from Example 85(0.211, 0.413 mmol). The bottle was then placed under 50 psi of hydrogenand shaken for 15 hours. The solution was then filtered through aCelite® pad, which was washed repeatedly with methanol and chloroform.The filtrate and washings were combined and concentrated to a yellowishoil. The oil was purified by flash chromatography on Merck silica gel in50% acetone in hexane. After concentrating the desired fractions,product A was obtained as a white foam (0.160 gm, 75%).

TLC: Rf 0.52 (50% acetone in hexane)

B.(S)-4-[[2-[2-Ethyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A dioxane solution (10 ml) of compound A (0.160 gm, 0.303 mmol) wastreated with a solution of NaOH (1M in H₂ O, 0.91 ml, 0.91 mmol) andthen heated to 55° C. for 3 hours. Additional NaOH (1M in H₂ O, 0.31 ml,0.31 mmol) was added to the solution, which was allowed to stir anotherhour. The solution was then concentrated to a white solid. The solid wasdissolved in water and chromatographed on HP-20 resin, eluting firstwith water (200 ml), then with 50% MeOH in water (400 ml), and finally,MeOH (200 ml). The desired fractions were pooled, concentrated, theresultant white solid dissolved in water and lyophilized to give Example92 as a fluffy white solid (0.100 g, 61%).

m.p. 295° C. (decomp) TLC: Rf 0.69 (6:3:1, n-propanol:NH₄ OH:H₂ O)Elemental Analysis for C₂₆ H₂₇ FNO₅ P×2Na×1.25H₂ O: Calc'd: C 56.57 H5.39 N 2.54 F 3.44 P 5.61 Found: C 56.53 H 5.02 N 2.24 F 3.47 P 5.51

Example 93(S,E)-4-[[2-[4-(4-Fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A.(E)-3-(2-Iodoethenyl)-4-fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenylpyridine

A mixture of(E)-3-[2-(Tributylstannyl)ethenyl]-4-(4-fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenylpyridine(7.18 gm, 24.7 mmol), acetylene 1 (4.500 gm, 13.7 mmol) and AIBN (0.084gm, 5.1 mmol) were heated at 140° C. for 1.5 hours. The solution wascooled to room temperature and diluted with ether (30 ml). Iodine (7.16gm, 27.1 mmol) was added and an unexpectedly strong exothermic reactionoccurred and approximately half the solution foamed out of the flask.The flask was recapped and allowed to stir 16 hours. The solution wasthen quenched with 10% Na₂ S₂ O₃ in saturated NaHCO₃. The solution wasdiluted with ether, washed with 10% Na₂ S₂ O₃ in saturated NaHCO₃(twice) and brine, then dried over Na₂ SO₄, filtered and concentrated toa yellow oil. The oil was purified by flash chromatography on Mercksilica gel in 1% EtOAc in hexane. The desired fractions were combinedand concentrated to afford a white solid, which was recrystallized fromhexane to give product A as hard, off-white crystals (2.830 gm, 45%).

m.p. 115°-117° C. Elemental Analysis for C₂₃ H₂₁ FIO₅ : Calc'd: C 60.4 H4.63 N 3.06 F 4.15 I 27.75 Found: C 60.87 H 4.58 N 2.93 F 4.12 I 27.51

B.(S,E)-4-[[2-[4-(4-Fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

Vinyl iodide A (2.380 gm, 5.19 mmol) was added dropwise to a -78° C.solution of t-BuLi (1.7M in pentane, 6.11 ml, 10.4 mmol) in THF (10 ml)stirring under argon. The solution was allowed to stir 15 minutes at-78° C., then cooled to -100° C. and cannulated into a THF solution (15ml) of the chloridate from Example 57, part G, also cooled to -100° C.The solution was stirred 15 minutes at -100° C., quenched with saturatedNH₄ Cl and warmed to 0° C., after which saturated NaHCO₃ was added. Thesolution was diluted with ether and the organic layer washed with brine,dried over Na₂ SO₄, filtered and concentrated to give a dark orange oil.The oil was purified by flash chromatography on Merck silica gel in 60%EtOAc in hexane. Pure product fractions were combined and evaporated toafford compound B as a white, fluffy foam (1.230 gm, 35%).

TLC: Rf 0.39 (40% EtOAc in hexane)

C.(S,E)-4-[[2-[4-(4-Fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

(Bu)₄ NF (1M in THF, 5.40 ml, 5.40 mmol) was added to a solution ofsilyl ether B (1.230 gm, 1.80 mmol) and HOAc (0.54 ml, 9.43 mmol) in THF(20 ml) and allowed to stir 17 hours at room temperature. AdditionalTBAF (1.80 ml, 1.80 mmol and HoAC (0.172 ml, 3.2 mmol) were added to thereaction mixture, which was allowed to stir under argon another 3 hours.The solution was diluted with EtOAc and washed with 5% KHSO₄ (threetimes). The aqueous layers were extracted with EtOAc (twice) and theorganic layers were combined and washed with brine, then dried over Na₂SO₄, filtered and concentrated to give a clear oil. The oil was purifiedby flash chromatography on Merck silica gel in 35% acetone in hexane.Product fractions were pooled and concentrated to afford compound C as aclear oil (0.785 gm, 83%).

TLC: Rf 0.54 (50% acetone in hexane)

D.(S,E)-4-[[2-[4-(4-Fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

NaOH (1M in H₂ O, 2.26 ml, 2.26 mmol) was added dropwise to a solutionof compound C (0.335 gm, 0.64 mmol) in dioxane (10 ml), allowed to stirat room temperature for 1.5 hours, and then heated to 60° C. and stirredfor 1 hour. The mixture was then concentrated to a white solid. Thesolid was dissolved in water and chromatographed on HP-20 resin, elutingfirst with water (200 ml), then with 50% MeOH in water (400 ml), andfinally with MeOH (200 ml). The desired fractions were pooled,concentrated, and the resultant white solid dissolved in water andlyophilized to give Example 93 as a fluffy white solid (0.300 gm, 90%).

m.p. 312° C. (decomp) TLC: Rf 0.61 (6:3:1, n-propanol:NH₄ OH:H₂ O)Elemental Analysis for C₂₇ H₂₇ NFPO₅ Na₂ ×2.20 H₂ O: Calc'd: C 55.81 H5.45 N 2.41 F 3.27 P 5.33 Found: C 55.78 H 5.40 N 2.44 F 3.12 P 5.32Optical Rotation: [a]_(D) =+1.6° (MeOH, c=4.1 mg/ml)

Example 94(S)-4-[[2-[4-(4-Fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A.(S)-4-[[2-[4-(4-Fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

10% Pd/C (0.185 gm, 0.174 mmol) was added to a Parr bottle containing anargon-purged, MeOH (50 ml) solution of compound C from Example 93 (0.450gm, 0.854 mmol). The bottle was then placed under 50 psi of hydrogen andshaken for 3 hours. The solution was then filtered through a Celite®pad, which was washed repeatedly with methanol. The filtrate wasconcentrated to give a clear oil. The oil was purified by flashchromatography on Merck silica gel in 60% acetone in hexane. Afterconcentrating the desired fractions, product A was obtained as a whitefoam (0.300 gm, 67%).

TLC: Rf 0.50 (50% acetone in hexane)

B.(S)-4-[[2-[4-(4-Fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

Di-ester A (0.300 gm, 0.57 mmol) was dissolved in dioxane (10 ml) andtreated with NaOH (1M in H₂ O, 1.71 ml, 1.71 mmol). The solution washeated to 55° C. and allowed to stir 3 hours. The solution wasconcentrated to a white solid. The solid was dissolved in water andchromatographed on HP-20 resin, eluting first with water (200 ml), thenwith 50% MeOH in water (400 ml), and finally, MeOH (200 ml). The desiredfractions were pooled and concentrated, and the resultant white solidwas dissolved in water and lyophilized to give Example 94 as a fluffywhite solid (0.290 gm, 94%).

m.p. 312° C. (decomp) TLC: Rf 0.67 (6:3:1, n-propanol:NH₄ OH, H₂ O)Elemental Analysis for C₂₇ H₂₉ NFNa₂ PO₅ *1.75 H₂ O: Calc'd: C 56.39 H5.70 N 2.44 F 3.30 P 5.39 Found: C 56.71 H 5.52 N 2.35 F 3.11 P 5.23Optical Rotation: [a]_(D) =-1.9° (MeOH, c=4.3 mg/ml)

Example 95(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A. 3-Cyclopropyl-3-oxopropanoic acid, ethyl ester

To a slurry of NaH (60% in mineral oil, 19.200 g, 0.48 mol) in drydiethyl carbonate (80 ml) was added a solution of methyl cyclopropylketone (23.5 ml, 20.00 g, 0.238 mol) in Et₂ O (30 ml). After theaddition of approximately 10% of the ketone solution, EtOH (0.25 ml) wasadded and the addition of the ketone continued. Soon after the additionwas complete, the reaction became quite exothermic with vigorous H₂evolution. Periodic cooling with an ice bath was required. After onehour, H₂ evolution had ceased and the mixture was diluted with Et₂ O(200 ml) and hexane (185 ml). The solution was cooled in an ice bath andcarefully treated with 5% HCl (10 ml), at which time a thick slurrydeveloped. The solid was collected by filtration and washed with hexane.The solid was then partitioned between Et₂ O and 5% HCl until all of thesolid had dissolved and the aqueous layer remained acidic. The organiclayer was separated and washed with H₂ O, saturated NaHCO₃, and brine,then dried (MgSO₄), filtered and stripped. The liquid residue wassubjected to flash chromatography (Merck SiO₂, 20% EtOAc in hexane) toprovide compound A (20.357 g, 55%) as a yellow liquid.

TLC: R_(f) =0.24 (20% EtOAc in hexane).

B. 3-(4-Fluorophenyl)-1-phenyl-2-propen-1-one

A solution of benzaldehyde (19.220 g, 181 mmol) and p-fluoroacetophenone(25.000 g, 181 mmol) in ethanol (200 ml) was treated with sodiummethoxide (1.972 g, 36.5 mmol). A precipitate fell out of solution after30 minutes. After stirring at room temperature for 15 hours, thesolution was treated with 50 ml of H₂ O, cooled in an ice bath, andfiltered. The solid was rinsed with cold ethanol and dried under highvacuum to yield compound B (29.730 g, 73%) as a yellow crystallinesolid.

Melting point: 76.3°-77.5° TLC: R_(f) =0.46 (20% EtOAc in hexane)Microanalysis for C₁₅ H₁₁ FO: Calc'd: C 79.63, H 4.90, F 8.40 Found: C79.57, H 4.77, F 8.30

C. α-Cyclopropylcarbonyl-β-(4-fluorophenyl)-Δ-oxobenzenepentanoic acid,ethyl ester

A mixture of compound B (7.280 g, 32.2 mmol) and compound A (6.00 g,38.4 mmol) in absolute EtOH (100 ml) was treated with a solution ofEtONa in EtOH (21% by weight solution, 1.28 g, 4.8 mmol). After stirringat room temperature for 30 minutes, a thick precipitate fell out ofsolution. Additional EtOH (40 ml) was added and stirring continued foran hour. The solution was treated with acetic acid (0.28 ml) and cooledto 0° C. The solid was collected by filtration, washed with cold EtOHand hexane, and dried in vacuo to give compound C, a mixture ofdiastereomers, as a white amorphous solid (10.295 g, 84%).

m.p. 114°-117° C. TLC: R_(f) 0.21 (20% EtOAc in hexane)

D. 2-Cyclopropyl-4-(4-fluorophenyl)-6-phenyl-3-pyridinecarboxylic acid,ethyl ester

A mixture of compound C (10.113 g, 26.4 mmol), NH₄ OAC (6.142 g, 79.7mmol) and Cu(OAc)₂ (13.920 g, 70.0 mmol) in glacial HOAc (70 ml) washeated at 110° C. for 0.5 hours. Additional NH₄ OAc (2.10 g) was added,and heating continued for four more hours. The solution was cooled toroom temperature and subsequently poured into an ice cold mixture ofconcentrated NH₄ OH (85 ml) in H₂ O (150 ml). The mixture was extractedwith Et₂ O and the Et₂ O extract was washed with H₂ O and brine, thendried (Na₂ SO₄), filtered and stripped to yield a yellow oil whichsolidified on standing. Recrystallization from EtOAc/hexane affordedcompound D as a pale yellow solid (7.810 g). The mother liquor wasflashed (Merck SiO₂, 10% EtOAc in hexane) to five additional product,which was recrystallized from hexane (477 mg). Total pooled solids(8.287 g, 87%).

m.p. 89.5°-92° C. TLC: R_(f) 0.50 (20% EtOAc in hexane) Microanalysisfor C₂₃ H₂₀ FNO₂ : Calc'd: C 76.43 H 5.58 N 3.88 F 5.26 C 76.40 H 5.58 N3.70 F 5.15

E. 2-Cyclopropyl-4-(4-fluorophenyl)-6-phenyl-3-pyridinemethanol

A cold (0° C.) solution of ester D (7.798 g, 21.6 mmol) in dry THF (200ml) was treated with LiAlH₄ (2.378 g, 62.7 mmol). Ten minutes after theaddition, the cooling bath was removed and the mixture was stirred atroom temperature for one hour. The solution was recooled to 0° C. andquenched in succession with H₂ O (2.5 ml), 10% NaOH (4.0 ml), and H₂ O(7.5 ml). The solution was filtered and the salts were washed withEtOAc. Removal of the filtrate solvent afforded a solid. The solid wasrecrystallized from EtOAc and Et₂ O. Removal of the filtrate solventafforded a solid. The solid was recrystallized from EtOAc/hexane toprovide compound E (5.866 g, 85%) as an amorphous white solid.

m.p. 176°-177° C. TLC: R_(f) 0.53 (40% EtOAc in hexane) Microanalysisfor C₂₁ H₁₈ FNO: Calc'd:C 78.97 H 5.68 N 4.39 F 5.95 Found: C 78.72 H5.67 N 4.23 F 5.67

F. 2-Cyclopropyl-4-(4-fluorophenyl)-6-phenyl-3-pyridinecarboxaldehyde

A solution of 4-methylmorpholine N-oxide (2.982 g, 25.5 mmol) in CH₂ Cl₂(80 ml) was dried over MgSO₄ for 15 minutes. The solution was filtereddirectly into a 500 ml flask, using approximately 20 ml CH₂ Cl₂ toeffect transfer. The flask was then charged with dry 4A molecular sieves(10.4 g), alcohol E (4.012 g, 12.56 mmol), and tetrapropylammoniumperruthenate (222 mg, 0.63 mmol). After stirring at room temperature for40 minutes, the black solution was diluted with Et₂ O (120 ml), stirredfor 5 minutes, then filtered through Celite®. The filtrate was strippedand the dark residue was dissolved in CH₂ Cl₂ and flashed (Merck SiO₂,20% EtOAc in hexane) to give the product as a solid. The solid wasrecrystallized from EtOAc/hexane (2 crops) to give compound F (3.115 g,78%) as a yellow solid.

m.p. 110°-113° C. TLC: R_(f) 0.52 (20% EtOAc in hexane)

G.2-Cyclopropyl-3-(2,2-dibromoethenyl)-4-(4-fluorophenyl)-6-phenylpyridine

A solution of carbon tetrabromide (4.245 g, 12.8 mmol) in CH₂ Cl₂ (10ml) was added over a 9 minute period to a cold (0° C.) solution ofaldehyde F (2.725 g, 8.6 mmol) and triphenylphosphine (6.761 g, 25.8mmol) in CH₂ Cl₂ (35 ml). After the addition was complete, the coolingbath was removed and the mixture was stirred at room temperature for 25minutes. The solution was quenched with saturated NaHCO₃ and extracted 2times with CH₂ Cl₂. The combined organic layers were dried (Na₂ SO₄),filtered and concentrated. The concentrate was chromatographed (flash,Merck SiO₂, 35% CH₂ Cl₂ in hexane) to give impure dibromide G as asolid. Recrystallization from EtOAc/hexane (2 crops) provided compound G(3.588 g, 88%) as fine white needles.

H.(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, ethyl ester

A solution of dibromide G (1.000 g, 2.11 mmol) in THF (7 ml) was addeddropwise to a solution of n-BuLi (2.5M in hexane, 1.8 ml, 4.5 mmol) inTHF (10 ml) at -78° C. over a 6-minute period. The resulting clearyellow solution was stirred at -78° C. for 40 minutes, then addeddropwise via cannula over a 10-minute period to a -78° C. solution ofthe phosphonochloridate from Example 57, part G in THF (15 ml). Theresulting greenish mixture was stirred at -78° C. for 20 minutes, thenquenched with 50% saturated NH₄ Cl. The solution was warmed to 0° C.,diluted with H₂ O, and poured into saturated NaHCO₃. The aqueous phasewas extracted once with Et₂ O. The Et₂ O layer was washed with brine,dried (Na₂ SO₄), filtered and stripped to give a yellow oil. The residuewas chromatographed (flash, Merck SiO₂, 40% EtOAc in hexane) to affordcompound H as a white foam (1.270 g, 81%).

TLC: R_(f) =0.25 (40% EtOAc in hexane).

I.(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, ethyl ester

A mixture of compound H (1.255 g, 1.68 mmol) and HOAc (490 μl, 5.14 mg,8.6 mmol) in THF (25 ml) was treated with tetra-n-butylammonium fluoride(1.0M in THF, 8.2 ml, 8.2 mmol). After stirring at room temperature for16 hours, the solution was diluted with EtOAc and washed three timeswith 5% KHSO₄. The EtOAc layer was washed with brine, dried (Na₂ SO₄),filtered and stripped to afford a yellow oil. The oil was dissolved inEt₂ O, cooled to 0° C. and treated with excess diazomethane for 15minutes. The excess diazomethane was destroyed by the addition of HOAcand the solvent was removed in vacuo. The residue was chromatographed(flash, Merck SiO₂, 1:1--acetone:hexane) to afford intermediate I (746mg, 87%) as a white foam.

TLC: R_(f) =0.30 (1:1--acetone:hexane)

J.(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A solution of intermediate I (730 mg, 1.44 mmol) in dioxane (6 ml) wastreated with 1N NaOH (5.0 ml, 5.0 mmol) at room temperature and themixture was subsequently heated at 60° C. under argon for 0.5 hour. Thesolvent was evaporated and the residue was chromatographed on HP-20eluting in succession with H₂ O (200 ml) and 50% MeOH in H₂ O (200 ml).The desired fractions were pooled and evaporated and the residue wastaken up in H₂ O and lyophilized to give Example 95 (674 mg, 84%) as awhite solid.

m.p. decomp. ≧285° C. TLC: R_(f) =0.07 (8:1:1--CH₂ Cl₂ :HOAc:MeOH)Microanalysis for C₂₆ H₂₁ FNNa₂ O₅ P* 2.0 H₂ O: Calc'd: C 55.82, H.4.51; N 2.50; F 3.40; P 5.54 Found: C 55.84, H. 4.28; N 2.46; F 3.33; P5.50 Rotation [α]_(D) =+5.6° (MeOH, 9.8 mg in 1.21 ml)

Example 96(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A. 2-Cyclopropylcarbonyl-3-(4-fluorophenyl)-2-propenoic acid, ethylester

A mixture of 4-fluorobenzaldehyde (4.768 g, 38.4 mmol), the compoundfrom Example 95, part A (6.000 g, 38.4 mmol), piperidine (380 μl), andHOAc (75 μl) was refluxed in benzene (40 ml) with removal of water(Dean-Stark trap) for 16 hours. The cooled mixture was diluted with Et₂O and washed successively with 5% HCl, saturated NaHCO₃, H₂ O, andbrine, then dried (Na₂ SO₄), filtered, and stripped to yield an oil.Distillation of the oil (bp 127°-135° C. at 0.2 mm Hg) afforded compoundA (9.299 g, 82%) as a pale yellow liquid.

TLC: R_(f) =0.31 (20% EtOAc in hexane) Microanalysis for C₁₅ H₁₅ FO₃ :Calc'd: C 68.69; H 5.76; F 7.24 Found: C 68.92; H 5.90; F 7.25

B.α-Cyclopropylcarbonyl-β-(4-fluorophenyl)-γ-methyl-Δ-oxobenzenepentanoicacid, ethyl ester

A -78° C. solution of LiN(TMS)₂ (1.0M in THF, 38 ml, 38 mmol) in dry THF(40 ml) was treated with a solution of propiophenone (5.015 g, 37.4mmol) in THF (6 ml) over a 4-minute period. After 30 minutes, a solutionof compound A (7.842 g, 29.9 mmol) in THF (15 ml) was added dropwise tothe above solution. After one hour, the mixture was quenched with aceticacid (2.5 ml) and saturated NH₄ Cl and warmed to room temperature. Themixture was diluted with H₂ O and subsequently extracted once with Et₂O. The Et₂ O extract was washed with brine, dried (Na₂ SO₄), filteredand stripped to give an oil. The oil was transferred to a round bottomflask which was fitted with a short path distillation apparatus and theoil was heated at 65° C. at 0.2 mm Hg to remove the volatiles and excesspropiophenone. The pot residue, crude compound B was used directly inthe next reaction.

C.2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinecarboxylicacid, ethyl ester

A mixture of crude compound B, NH₄ OAc (9.210 g, 119.5 mmol), andCu(OAc)₂ (17.921 g, 89.8 mmol) in glacial HOAc (80 ml) was heated at110° C. for 21 hours. The solution was cooled to room temperature andsubsequently poured into an ice cold mixture of concentrated NH₄ OH (100ml) in H₂ O (200 ml). The mixture was extracted twice with Et₂ O and thepooled Et₂ O extracts were washed with H₂ O and brine, then dried (Na₂SO₄), filtered and stripped to yield a brown solid. The solid wasdissolved in CH₂ Cl₂ and flashed (Merck SiO₂, 20% EtOAc in hexane) togive compound C as a reddish oil which readily solidified.Recrystallization from EtOAc/hexane (2 crops) afforded ester compound C(9.615 g, 86%) as white crystals.

m.p. 113°-114.5° C. TLC: R_(f) =0.46 (20% EtOAc in hexane) Microanalysisfor C₂₄ H₂₂ FNO₂ : Calc'd: C 76.78; H 5.91; N 3.73; F 5.06 Found: C76.68; H 5.92; N 3.63; F 5.06

D.(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A cold (0° C.) solution of ester C (8.942 g, 23.8 mmol) in dry THF (200ml) was treated with LiAlH₄ (2.701 g, 71.2 mmol). Ten minutes after theaddition, the cooling bath was removed and the mixture was stirred atroom temperature for 1.5 hours. The solution was recooled to 0° C. andquenched in succession with H₂ O (3.0 ml), 10% NaOH (4.5 ml), and H₂ O(8.5 ml). The solution was filtered and the salts were washed with EtOAcand Et₂ O. Removal of the filtrate solvent afforded an oily solidresidue. The residue was dissolved in Et₂ O, diluted with hexane, heatedto remove the Et₂ O, and cooled to provide compound D (6.548 g, 83%) asan amorphous white solid.

m.p. 140.5°-142° C. TLC: R_(f) =0.18 (20% EtOAc in hexane) Microanalysisfor C₂₂ H₂₀ FNO: Calc'd: C 79.25; H 6.05; N 4.20; F 5.70 Found: C 79.14;H 5.99; N 4.15; F 5.73

E.2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinecarboxaldehyde

A solution of 4-methylmorpholine N-oxide (4.002 g, 34.2 mmol) in CH₂ Cl₂(130 ml) was dried over MgSO₄ for 15 minutes. The solution was filtereddirectly into a 500-ml flask, using approximately 30 ml CH₂ Cl₂ toeffect the transfer. The flask was then charged with dry 4A molecularsieves (16 g), alcohol D (5.686 g, 17.05 mmol), and tetrapropylammoniumperruthenate (301 mg, 0.86 mmol). After stirring at room temperature for30 minutes, the black solution was diluted with Et₂ O (200 ml), stirredfor 5 minutes, then filtered through a plug of silica gel (Merck, 65×30mm) washed with Et₂ O. The filtrate was stripped to give a pale yellowsolid. The solid was recrystallized from EtOAc/hexane to give compound E(3.982 g) as white crystals. Flashing the mother liquor (Merck SiO₂, 20%EtOAc in hexane) gave additional product, which was recrystallized fromhexane (499 mg). Total pooled solids, 4.481 g (79%).

m.p. 137°-139° C. TLC: R_(f) =0.50 (20% EtOAc in hexane) Microanalysisfor C₂₂ H₁₈ FNO: Calc'd: C 79.74; H 5.47; N 4.23; F 5.73 Found: C 79.32;H 5.49; N 4.13; F 5.65

F.2-cyclopropyl-3-(2,2-dibromoethenyl)-4-(4-fluorophenyl)-5-methyl-6-phenylpyridine

A solution of carbon tetrabromide (5.810 g, 17.5 mmol) in CH₂ Cl₂ (9 ml)was added over a 12-minute period to a cold (0° C.) solution of aldehydeE (3.864 g, 11.7 mmol) and triphenylphosphine (9.191 g, 35.0 mmol) inCH₂ Cl₂ (60 ml). After the addition was complete, the cooling bath wasremoved and the mixture was stirred at room temperature for 20 minutes.The solution was quenched with saturated NaHCO₃ (40 ml) and extractedtwice with CH₂ Cl₂. The combined organic layers were dried (Na₂ SO₄),filtered and concentrated. The concentrate was chromatographed (flash,Merck SiO₂, 40% CH₂ Cl₂ in hexane) and the pure desired fractions werestripped to give a solid. Recrystallization from EtOAc/hexane (2 crops)provided compound F (5.432 g, 96%) as white crystals.

m.p. 155°-157° C. TLC: R_(f) =0.58 (20% EtOAc in hexane). Microanalysisfor C₂₃ H₁₈ Br₂ FN: Calc'd: C 56.70; H 3.72; N 2.88; F 3.90; Br 32.80Found: C 56.55; H 3.68; N 2.82; F 3.89; Br 32.72

G.(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, ethyl ester

A solution of dibromide F (1.000 g, 2.05 mmol) in THF (5 ml) was addeddropwise to a solution of n-BuLi (2.5M in hexane, 1.73 ml, 4.3 mmol) inTHF (10 ml) at -78° C. over a 10-minute period. The resulting paleyellow solution was stirred at -78° C. for one hour, then added dropwisevia cannula over a 12-minute period to a -78° C. solution of thephosphonochloridate from Example 57, part G in THF (15 ml). Theresulting mixture was stirred at -78° C. for 30 minutes, then quenchedwith 50% saturated NH₄ Cl. The solution was warmed to 0° C., dilutedwith H₂ O, and poured into saturated NaHCO₃. The aqueous phase wasextracted once with Et₂ O. The Et₂ O layer was washed with brine, dried(Na₂ SO₄), filtered and stripped to give an oil. The residue waschromatographed (flash, Merck SiO₂, 50% EtOAc in hexane) to affordcompound G as a white foam (1.158 g, 74%).

TLC: R_(f) =0.27 (40% EtOAc in hexane)

H.(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethynyl]methoxyphosphinyl]-3-hydroxybutanoicacid, ethyl ester

A mixture of compound G (1.148 g, 1.51 mmol) and HOAc (460 μl, 482 mg,8.0 mmol) in THF (25 ml) was treated with tetra-n-butylammonium fluoride(1.0M in THF, 7.6 ml, 7.6 mmol). After stirring at room temperature for17 hours, the solution was diluted with EtOAc and washed three timeswith 5% KHSO₄. The pooled aqueous extracts were back-extracted once withEtOAc and the combined EtOAc layers were washed with brine, dried (Na₂SO₄), filtered and stripped to afford a yellow oil. The oil wasdissolved in Et₂ O, cooled to 0° C. and treated with excess diazomethanefor 15 minutes. The excess diazomethane was destroyed by the addition ofHOAc and the solvent was removed in vacuo. The residue waschromatographed (flash, Merck SiO₂, 40% acetone in hexane, followed by40% hexane in acetone) to afford compound H (684 mg, 87% as a whitefoam.

TLC: R_(f) =0.37 (1:1--acetone:hexane)

I.(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A solution of compound H (672 mg, 1.29 mmol) in dioxane (7 ml) wastreated with 1N NaOH (4.5 ml, 4.5 mmol) at room temperature and themixture was subsequently heated at 60° C. under argon for one hour. Thesolvent was evaporated and the solid residue was dissolved in warm H₂ Oand chromatographed on HP-20, eluting in succession with H₂ O (150 ml)and 50% MeOH in H₂ O (200 ml). The desired fractions were pooled andevaporated and the residue was taken up in H₂ O and lyophilized to giveExample 96 (640 mg, 89%) as a white solid.

m.p. decomp. ≧295° C. TLC: R_(f) =0.07 (8:1-1--CH₂ Cl₂ :HOAc:MeOH)Microanalysis for C₂₇ H₂₃ FNNa₂ O₅ P * 1.25 H₂ O Calc'd: C 57.92; H4.59; N 2.50; F 3.39; P 5.53 Found: C 58.05; H 4.50; N 2.35; F 3.38; P5.72 Rotation: [α]_(D) =+8.8° (MeOH, 7.6 mg in 1.22 ml)

Example 97(S,E)-4-[[2-[2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A.2-Cyclopropyl-3-(2-ethynyl)-4-(4-fluorophenyl)-5-methyl-6-phenylpyridine

The compound from Example 96, part F (4.000 g, 8.21 mmol) in dry THF (12ml) was added to a solution of n-BuLi (2.5M in hexanes, 7.40 ml, 18.5mmol) in THF (35 ml) over a 6-minute period. After stirring at -78° C.for 50 minutes, the lime-green solution was quenched with saturated NH₄Cl and warmed to room temperature. The colorless mixture was dilutedwith H₂ O and extracted with Et₂ O. The organic layer was washed withbrine, dried (Na₂ SO₄), filtered and stripped to give a white solid. Thesolid was recrystallized from hexane to give very pale lavender-coloredneedles (1st crop 2.062). From the mother liquor was obtained a second(392 mg) and third crop (151 mg) of pure product. Total pooled solids(compound A) were 2.064 g, 97%.

m.p.: 140°-142° C. TLC: R_(f) =0.55 (EtOAc in hexane) Analysis for C₂₃H₁₈ FN: Calc'd: C 84,38; H 5.54; N 4.28; F 5.80 Found: C 84.42; H 5.45,N 4.44; F 5.88

B.2-Cyclopropyl-3-(2-iodoethenyl)-4-(4-fluorophenyl)-5-methyl-6-phenylpyridine

A mixture of compound A (1.400 g, 4.28 mmol) and AIBN (20 mg) intri-n-butylstannyl hydride (2.4 ml, 2.60 g, 8.9 mmol) was rapidly heatedto 140° C. by immersion in a pre-heated oil bath. Approximately 20 mg ofAIBN was added to the reaction mixture after 0.5 hour and again one hourafter heating was initiated. After 1.5 hours, the dark orange mixturewas cooled to room temperature, diluted with Et₂ O (40 ml) and treatedwith 2,6-lutidine (1.30 ml, 1.19 g, 11.2 mmol) followed by solid I₂(3.27 g, 12.9 mmol). The dark reaction mixture was stirred for 60minutes, then poured into a 50% saturated NaHCO₃ solution containing 3.6g Na₂ S₂ O₃. The layers were shaken and separated. The ethereal layerwas washed successively with H₂ O, 4.5M NH₄ OH, H₂ O, and brine, thendried (Na₂ SO₄), filtered and stripped to yield an oil. The residue wassubjected to flash chromatography (Merck SiO₂, 10% EtOAc in hexane) toafford crude compound B as a solid. Recrystallization from hexane gavecompound B (1.288 g) as a yellow solid. The mother liquor was flashed(Merck SiO₂, 5% EtOAc in hexane) and the desired fractions were pooled,stripped, and recrystallized from hexane to give additional product (235mg). Total yield of pure compound C 1.523 g, 78%.

m.p.: 134°-136° C. TLC: R_(f) =0.45 (10% EtOAC in hexane) Microanalysisfor C₂₃ H₁₉ FIN: Calc'd: C 60.67; H 4.21; N 3.08; F 4.17; I 27.87 Found:C 60.76; H 4.19; N 2.92; F 4.26; I 27.90

C.(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

A solution of the vinyl iodide from part B (1.300 g 2.85 mmol) in THF (6ml) was added over a 5-minute period to a -100° C. solution oft-butylithium (1.7M in pentane, 3.50 ml, 5.95 mmol) in THF (8 ml). Theresulting deep muddy red solution was stirred for 20 minutes, then addedover a 10-minute period to a -100° C. solution of thephosphonochloridate from Example 57, part G in THF (15 ml). Theresulting yellow mixture was stirred at minus 100° C. for 30 minutes,then quenched with 50% saturated NH₄ Cl. The solution was warmed to roomtemperature, diluted with H₂ O, and poured into saturated NaHCO₃. Theaqueous phase was extracted with Et₂ O. The Et₂ O extract was washedwith brine, dried (Na₂ SO₄), filtered and stripped. The resulting yellowoil was chromatographed (flash, Merck SiO₂, EtOAc in hexane) to affordcompound C as an oily foam (1.056 g, 49%).

TLC: R_(f) =0.19 & 0.14 (40% EtOAc in hexane)

D.(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]-3-hydroxybutanoicacid, methyl ester

A solution of compound C (1.030 g, 1.35 mmol) in THF (20 ml) was treatedwith HOAc (400 μl, 420 mg, 7.0 mmol) and tetra-n-butyl-ammonium fluoride(1.0M in THF, 6.7 mmol). After stirring at room temperature for 16hours, the solution was poured into saturated NaHCO₃ and extracted withEtOAc. The EtOAc extracted with washed with brine, dried (Na₂ SO₄),filtered, and stripped to give an oil, which was subsequentlychromatographed (flash, Merck SiO₂, 1:1--acetone:hexane followed by5:2--acetone:hexane). Compound D (647 mg, 92%) was obtained as an oilyfoam.

TLC: R_(f) =0.31 (1:1--acetone:hexane)

E.(S,E)-4-[[2-[2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A solution of compound D (320 mg, 0.61 mmol) in dioxane (4.5 ml) wastreated with 1N NaOH (2.1 ml, 2.1 mmol) and the mixture was stirred at50° C. for 1.75 hours. The solvent was evaporated and the residue wastaken up in H₂ O and chromatographed on HP-20, eluting in successionwith H₂ O (150 ml) and 50% MeOH in H₂ O (200 ml). The desired fractionswere pooled and evaporated and the residue was taken up in H₂ O andlyophilized to give Example 97 (292 mg, 85%) as a white solid.

m.p.: 310° C. (decomp.); [α]_(D) =+6.7° (MeOH, 6.3 mg in 1.25 ml) TLC:R_(f) =0.08 (8:1:1--CH₂ Cl₂ :HOAc:MeOH) Microanalysis for C₂₇ H₂₅ FNNa₂O₅ P * 1.33 H₂ O: Calc'd: C 57.56; H 4.95; N 2.49; F 3.37; P 5.50 Found:C 57.54; H 4.99; N 2.51; F 3.54; P 5.70

Example 98(S)-4-[[2-[2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethyl]hydroxyphosphinyl[-3-hydroxybutanoicacid, disodium salt

A.(S)-4-[[[2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A mixture of compound D from Example 96 (308 mg, 0.59 mmol) and Pd oncarbon (10% Pd on C, 129 mg) in MeOH (20 ml) was shaken under 50 psi ofH₂ for 7 hours. The solution was filtered, stripped, and chromatographed(flash, Merck SiO₂, 14:11--acetone hexane followed by 100% acetone) togive compound A (271 mg, 87%) as a colorless oil.

TLC: R_(f) =0.29 (1:1--acetone:hexane)

B.(S)-4-[[2-[2-Cyclopropyl-4-(4-fluorophenyl)-5-methyl-6-phenyl-3-pyridinyl]ethyl]hydroxyphosphinyl[-3-hydroxybutanoicacid, disodium salt

A solution of compound A (260 mg, 0.495 mmol) in dioxane (3 ml) wastreated with 1N NaOH (1.8 ml, 1.8 mmol) and the mixture was stirred at50° C. for 2.5 hours. The solvent was evaporated and the residue waschromatographed on HP-20, eluting in succession with H₂ O (150 ml) and50% MeOH in H₂ O (150 ml). The desired fractions were pooled andevaporated and the residue was taken up in H₂ O and lyophilized to giveExample 98 (242 mg, 87%) as a white solid.

m.p.: 300° C. (decomp.); [α]_(D) =-0.3° (MeOH, 4.0 mg in 1.25 ml) TLC:R_(f) =0.09 (8:1:1--CH₂ Cl₂ :HOAc:MeOH) Microanalysis for C₂₇ H₂₇ FNNa₂O₅ P * 1.25 H₂ O: Calc'd: C 57.50; H 5.27; N 2.48; F 3.37; P 5.49 Found:C 57.46; H 5.23; N 2.38; F 3.38; P 5.61

Example 99(S)-4-[[[4-(4-Fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-benzo[6,7]cyclohepta[1,2-b]-pyridin-3-yl]methoxy]hydroxyphosphinyl]-3-hydroxybutanoicacid, disodium salt

A.(S)-4-[[[4-(4-Fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-3-yl)methoxy]methoxyphosphinyl]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoicacid, methyl ester

The phosphonochloridate from Example 57, part G (2.157 g, 3.41 mmol) waspartitioned between EtOAc and 5% KHSO₄. The EtOAc layer was washed threetimes with 5% KHSO₄, then with brine, then dried (Na₂ SO₄), filtered andstripped to give a colorless oil (phosphonic acid monomethyl ester). Theoil was dissolved in dry CH₂ Cl₂ (20 ml) and treated withN,N-diethyltrimethylsilylamine (0.992 g, 6.85 mmol). After stirring atroom temperature for one hour, the solvent was removed in vacuo and theresidue was azeotroped with dry toluene (20 ml). The residue wasre-dissolved in dry CH₂ Cl₂ (20 ml), cooled to 0° C. and treated withDMF (0.050 g, 0.68 mmol) and oxalyl chloride (0.52 g, 4.10 mmol). After15 minutes, the solution was warmed to room temperature and stirred foran additional 45 minutes. The solvent was stripped and the yellowresidue was azeotroped with toluene (20 ml) and dried in vacuo (oilpump) for 1 hour. The residue was then dissolved in pyridine (15 ml) andthe temperature of the solution was lowered to 0° C. A pyridine solution(5 ml) of compound C from Example 63 (0.691 g, 1.91 mmol) was then addedto the flask dropwise and the solution was allowed to stir 17 hours at0° C. The reaction was then quenched with saturated NH₄ Cl, and themixture diluted with EtOAc (50 ml). The organic layer was washed withwater and brine, then dried over Na₂ SO₄, filtered and concentrated toan amber oil. The oil was purified by flash chromatography on Mercksilica gel in 30% EtOAc in hexane. After combination and concentrationof those fractions containing product, compound A was obtained as ayellow oil (0.604 g, 40%).

TLC: R_(f) =0.53 (40% EtOAc in hexane).

B.(S)-4-[[[4-(4-Fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-3-yl]methoxy]methoxyphosphinyl]-3-hydroxybutanoic acid,methyl ester

TBAF (1M in THF, 2.25 ml, 2.25 mmol) was added to a THF (20 ml) solutionof compound A (0.597 mmol) and acetic acid (0.180 g, 3.01 mmol), and thesolution was allowed to stir at room temperature for 17 hours. More TBAF(1.0M in THF, 1.12 g, 1.12 mmol) and HOAc (0.090 g, 1.50 mmol) wereadded to the solution, which stirred another 3 hours. The solution wasthen diluted with EtOAc (50 ml), washed with saturated NaHCO₃, water andbrine, dried over Na₂ SO₄, and filtered and concentrated to an orangeoil. The oil was purified by flash chromatography on Merck silica gel in40% acetone in hexane. Product fractions were combined and concentratedto afford compound B as a clear oil (0.404 g, 97%).

TLC: R_(f) =0.63 (50% acetone in hexane).

C.(S)-4-[[[4-(4-Fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-benzo[6,7]cyclohepto[1,2-b]pyridin-3-yl]methoxy]hydroxyphosphinyl]-3-hydroxybutanoic acid,disodium salt

An aqueous solution of NaOH (1M in H₂ O, 1.99 ml, 1.99 mmol) was addedto a solution of compound B (0.370 g, 0.67 mmol) in dioxane (10 ml). Themixture was stirred at 55° C. for 17 hours. The solution was thenconcentrated to a white solid. The solid was dissolved in hot H₂ O toform a white slurry. The slurry was applied to a column of HP20 gel, andthe column was eluted first with 200 ml H₂ O, then with 400 ml 30% MeOHin H₂ O. Those fractions containing the product were combined andconcentrated to a white solid. The solid was dissolved in water andlyophilized to afford Example 99 as a white, fluffy solid (0.280 g,73%).

Melting point: 300° C. (decomp). Elemental analysis for C₂₈ H₂₉ NFNa₂PO₆ *2.00 mole H₂ O Calc'd: C 55.36, H 5.47, N 2.31, F 3.13, P 5.10Found: C 55.65, H 5.38, N 2.19, F 3.12, P 5.17 Optical rotation: [a]_(D)=-0.3° (MeOH, c=3.8 mg/ml).

Examples 100 to 104

These examples were prepared following the procedures of Example 99,substituting the appropriate pyridine methanol to form the product. Theexamples follow the formula ##STR60## in which M is sodium and R¹ to R⁴are as defined in the table below.

    ______________________________________                                        Example  R.sup.1    R.sup.2  R.sup.3                                                                              R.sup.4                                   ______________________________________                                        100      4-F-C.sub.6 H.sub.4                                                                      i-C.sub.3 H.sub.7                                                                      C.sub.6 H.sub.5                                                                      H                                         101      4-F-C.sub.6 H.sub.4                                                                      i-C.sub.3 H.sub.7                                                                      C.sub.6 H.sub.5                                                                      CH.sub.3                                  102      4-F-C.sub.6 H.sub.4                                                                      i-C.sub.3 H.sub.7                                                                      C.sub.6 H.sub.5                                                                      CH.sub.2 CH.sub.3                         103      4-F-C.sub.6 H.sub.4                                                                      c-C.sub.3 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      CH.sub.3                                  104      4-F-C.sub.6 H.sub.4                                                                      CH.sub.2 CH.sub.3                                                                      C.sub.6 H.sub.5                                                                      CH.sub.3                                  ______________________________________                                    

Example 105

This example embodies reaction scheme 9. All reactions were carried outunder a static atmosphere of argon and stirred magnetically unlessotherwise noted. All reagents used were of commercial quality and wereobtained from Aldrich Chemical Co. Dry THF and Et₂ O were obtained bydistillation from the sodium ketyl of benzophenone under nitrogen. DryCH₂ Cl₂ were obtained by distillation from CaH₂ under nitrogen. Pyridineand dioxane were obtained from American Burdick and Jackson and werestored over 4 angstrom molecular sieves. All flash chromatographicseparations were performed using E. Merck silica gel (60, particle size,0.040-0.063 mm). Reactions were monitored by TLC using 0.25 mm E. Mercksilica gel plates (60 F₂₅₄).

A. 2-Methyl-1-(2aminophenyl)-1-propanone

A cold (0° C.) solution of anthranilonitrile (8.507 g, 72.0 mmol) in dryEt₂ O (30 ml) was treated dropwise with i-propylmagnesium chloride (2.0Min Et₂ O, 100 ml, 200 mmol) over a 15-minute period. After the additionwas complete, the mixture was warmed to room temperature and stirringcontinued for 4.5 hours. The solution was re-cooled to 0° C. andcarefully quenched by the addition of 10% HCl (150 ml). The mixture waswarmed to room temperature, stirred for 30 minutes, re-cooled to 0° C.and made basic by the addition of solid NaOH (25 g). The aqueous layerwas extracted with Et₂ O (3×200 ml) and the combined ethereal extractswere washed with brine (150 ml) and dried (Na₂ SO₄). The solution wasevaporated and the crude product was flash chromatographed on a silicagel column (50 cm×200 cm) using 15% EtOAc in hexane as the elutingsolvent mixture to afford compound A as a golden yellow oil (yield10.916 g, 92%); R_(f) 0.32 (20% EtOAc in hexane). Pure compound A mayalso be obtained in slightly diminished yield (75%) by directdistillation of the crude product (bp 86°-91° C./0.5 Torr).

Microanalysis for C₁₀ H₁₃ NO: Calc'd: C 73.58 H 8.03 N 8.58 Found: C73.57 H 8.01 N 8.94

B. 3-[[2-(2-Methyl-1-oxopropyl)phenyl]amino]-3-oxopropanoic acid, ethylester

A mixture of compound A (5.000 g, 30.6 mmol) and dry pyridine (7.4 ml),7.2 g, 91.5 mmol) in dry CH₂ Cl₂ (60 ml) at -78° C. was treated dropwisewith a solution of ethyl malonyl chloride (Aldrich, tech. grade, 4.62 g,30.7 mmol based on 100% purity) in CH₂ Cl₂ (10 ml) over a 15-minuteperiod. Thirty minutes after the addition, the reaction was quenchedwith H₂ O (50 ml) and warmed to room temperature. The mixture wasextracted with Et₂ O (150 ml) and the organic extract is washed insuccession with H₂ O (50 ml), 5% HCl (50 ml), H₂ O (50 ml), and brine(50 ml), then dried (Na₂ SO₄), filtered, and concentrated affording ared-brown oil. Flash column chromatography (50 cm×230 cm) of the crudeoil on silica gel using 25% EtOAc in hexane as the eluant providescompound B as a near-colorless oil; yield 5.620 g, (66%); R_(f) 0.49(40% EtOAc in hexane).

Microanalysis for C₁₅ H₁₉ NO₄ : Calc'd: C 64.96 H 6.91 N 5.05 Found: C64.94 H 6.80 N 6.40

C. 2-Hydroxy-4-(1-methylethyl)-3-quinolinecarboxylic acid, ethyl ester

A solution of compound B (4.555 g, 16.4 mmol) in absolute EtOH (65 ml)was treated with a solution of EtONa in EtOH (21% by weight, 1.8 g, 6.8mmol) and the mixture was stirred at room temperature for 5 minutes,then at reflux for 5 minutes. The solution was cooled and partitionedbetween EtOAc (200 ml) and 50% saturated NH₄ Cl (150 ml). The layerswere shaken and separated and the organic layer is washed with brine(2×75 ml) and dried (Na₂ SO₄). Filtration and solvent removal afforded asolid, which was recrystallized from EtOAc/hexane giving compound C (2crops) as fine white needles; yield 3.950 g, (93%); R_(f) 0.16 (40%EtOAc in hexane).

m.p. 195.2°-196.8° C. Microanalysis for C₁₅ H₁₇ NO₃ : Calc'd: C 69.48 H6.61 N 5.40 Found: C 69.47 H 6.61 N 5.38

D. 3-(Hydroxymethyl)-4-(1-methylethyl)-2-quinolinol

To a cold (0° C.) slurry of LiAlH₄ (1.624 g, 42.8 mmol) in dry THF (200ml) was added compound C (10.000 g, 38.6 mmol) portionwise as a solid(Caution: vigorous H₂ evolution). After stirring at 0° C. for 45minutes, the solution was carefully quenched by the successive additionof H₂ O (75 ml) and saturated NH₄ Cl (150 ml). The mixture was extractedwith EtOAc (2×150 ml) and the pooled organic extracts were washed withbrine (100 ml), dried (Na₂ SO₄), filtered and evaporated to provide ayellow solid. The solid residue was recrystallized from EtOAc, givingcompound D as a pale yellow amorphous solid (2 crops); yield 7.803 g,(93%); R_(f) 0.18 (1:1 acetone:hexane).

m.p. 149.5°-152.0° C. Microanalysis for C₁₃ H₁₅ NO₂ : Calc'd: C 71.86 H6.96 N 6.45 Found: C 71.61 H 6.94 N 6.31

E. 2-Hydroxy-4-(1-methylethyl)-3-quinolinecarboxaldehyde

A mixture of compound D (3.000 g, 13.8 mmol) and MnO₂ (Aldrich,activated type, 4.02 g, 46.2 mmol) in CH₂ Cl₂ (100 ml) was stirred atroom temperature for 24 hours. The reaction was treated with additionalMnO₂ (3.00 g, 34.5 mmol) and the mixture was subsequently refluxed for 3days. After cooling to room temperature, the solution is filteredthrough a Celite® pad, which was washed with CH₂ Cl₂. Evaporation of thefiltrate solvent gives a greenish solid which is dissolved in acetoneand filtered through a plug of silica gel (100 g), washing with 1:1acetone:hexane. The filtrate is stripped and the residue isrecrystallized from EtOAc/hexane affording compound E (two crops) asbright yellow crystals (2.512 g, 85% yield); R_(f) 0.44 (1:1acetone:hexane).

m.p. 177.0°-179.0° C. Microanalysis for C₁₃ H₁₃ NO₂ : Calc'd: C 72.54 H6.09 N 6.51 Found: C 72.42 H 6.03 N 6.32

F.4-(1-Methylethyl)-2-[[(trifluoromethyl)sulfonyl]oxy]-3-quinolinecarboxaldehyde

A bright yellow solution of compound E (1.961 g, 9.1 mmol) and drypyridine (2.20 ml, 2.15 g, 27.2 mmol) in dry CH₂ Cl₂ (33 ml) is cooledto 0° C. and subsequently treated dropwise with neattrifluoromethanesulfonic anhydride (1.80 ml, 3.02 g, 10.7 mmol) over a5-minute period. After stirring for 1.75 hours at 0° C., the tansolution is partitioned between Et₂ O (100 ml) and saturated NaHCO₃ (60ml). The layers are shaken and separated and the organic layer is washedwith brine (50 ml), dried (Na₂ SO₄), filtered, and stripped. The residueis flash chromatographed on a silica gel column (50 cm×160 cm) using 20%EtOAc in hexane as the eluting solvent mixture to afford compound F as awhite solid. Recrystallization of the solid from hexane gives theproduct as cubic crystals; yield 2.836 g, (90%); R_(f) 0.34 (20% EtOAcin hexane).

m.p. 69°-71° C. Microanalysis for C₁₄ H₁₂ F₃ NO₄ S: Calc'd: C 48.41 H3.48 N 4.03 F 16.33 S 9.23 Found: C 48.40 H 3.26 N 3.79 F 16.04 S 9.18

G. 2-(4-Fluorophenyl)-4-(1-methylethyl)-3-quinolinecarboxaldehyde

A mixture of compound F (2.000 g, 5.76 mmol),(4-fluorophenyl)tributylstannane (2.400 g, 6.23 mmol) prepared byreaction of the corresponding lithium or Grignard reagent withtri-n-butyltin chloride in Et₂ O at -78° C.), anhydrous LiCl (832 mg,19.6 mmol), and BHT (50 mg) in dry dioxane (35 ml) was treated with(PPh₃)₄ Pd (200 mg, 0.17 mmol) at room temperature. The temperature ofthe reaction was slowly raised to 100° C. over a 2-hour period andheating was continued for 13 hours. The dark mixture was cooled to roomtemperature and partitioned between Et₂ O (100 ml) and H₂ O (75 ml). Thelayers were shaken and separated and the organic layer is washed insuccession with H₂ O (50 ml), 15% NH₄ OH (75 ml), H₂ O (50 ml), andbrine (50 ml), then dried (Na₂ SO₄), filtered, and stripped. Theresidual yellow oil was flash-chromatographed on a silica gel column (50cm×150 cm) using 15% EtOAc in hexane as the eluting solvent mixture toafford the desired product as a pale yellow oil that solidified onstanding. Recrystallization of the solid from hexane (2 crops) gavecompound G as pale yellow needles; yield 1.597 g, (95%); R_(f) 0.45 (20%EtOAc in hexane).

m.p. 69.3°-71.5° C. Microanalysis for C₁₉ H₁₆ FNO: Calc'd: C 77.79 H5.50 N 4.78 F 6.48 Found: C 77.83 H 5.44 N 4.82 F 6.43

The abbreviations used herein have the following meanings:

    ______________________________________                                        HOAc          Acetic Acid                                                     Et.sub.2 O    Diethyl Ether                                                   THF           Tetrahydrofuran                                                 EtOH          Ethanol                                                         LAH           Lithium Aluminum Hydride                                        LiAlH.sub.4   Lithium Aluminum Hydride                                        DIBAL-H       Diisobutyl Aluminum Hydride                                     DMF           Dimethylformamide                                               DMSO          Dimethyl Sulfoxide                                              MeONa         Sodium Methoxide                                                EtONa         Sodium Ethoxide                                                 KOBu.sub.t    Potassium t-butoxide                                            NaH           Sodium Hydride                                                  LDA           Lithium Diisopropylamide                                        LiTMP         Lithium Tetramethylpiperidide                                   LiN(TMS).sub.2                                                                              Lithium Bistrimethylsilylamide                                  NH.sub.2 OH.HCl                                                                             Hydroxylamine Hydrochloride                                     NH.sub.4 OAc  Ammonium Acetate                                                Cu(OAc).sub.2 Copper (II) Acetate                                             MeOH          Methanol                                                        Pd            Palladium                                                       Pt            Platinum                                                        Ru            Ruthenium                                                       EtOAc         Ethyl Acetate                                                   n-BuLi        n-Butyl Lithium                                                 BSTFA         Bis(trimethylsilyl)-                                                          trifluoroacetamide                                              TMSBr         Trimethylsilyl bromide                                          NMO           4-methyl morpholine N-oxide                                     TPAP          tetrapropylammonium                                                           perruthenate                                                    Pd/C          Palladium on carbon                                             BHT           Butylated hydroxytoluene                                        PPh.sub.3     Triphenylphosphine                                              TBAF          Tetrabutyl Ammonium Fluoride                                    (MeO).sub.2 POCHN.sub.2                                                                     Dimethyl Diazomethylphosphonate                                 CHCl.sub.3    Chloroform                                                      Bu.sub.3 SnH  Tri-n-butyl tin Hydride                                         Bu.sub.4 NF   Tetrabutylammonium fluoride                                     AIBN          α,α'-Azaisobutyrylnitrile                           TEA           Triethylamine                                                   ClSi(t-butyl)Ph.sub.2                                                                       t-Butyldiphenylsilyl Chloride                                   ClSi(t-butyl)Me.sub.2                                                                       t-Butyldimethylsilyl Chloride                                   ClSi Ph.sub.3 Triphenylsilyl Chloride                                         HF            Hydrofluoric Acid                                               m-CPBA        meta-Chloroperoxybenzoic Acid                                   CF.sub.3 CO.sub.3 H                                                                         Peroxytrifluoroacetic Acid                                      t-butylLi     t-Butyl Lithium                                                 (or t-BuLi)                                                                   EDTA          Ethylenediaminetetroacetic                                                    acid                                                            ______________________________________                                    

What is claimed is:
 1. A compound of the formula ##STR61## or apharmaceutically acceptable salt thereof wherein: Am is ##STR62## X is--(CH₂)_(a) --, --CH═CH--, --C.tbd.C-- or --CH₂ O--; R¹ and R² are thesame or different and are each independently selected from(i) hydrogen,(ii) alkyl, (iii) aryl, (iv) cycloalkyl, (v) aralkyl, (vi) aralkoxy,(vii) alkenyl, and (viii) cycloalkenyl; R³ is selected from(i) hydrogen,(ii) lower alkyl, (iii) aryl, (iv) cycloalkyl, (v) alkoxy, (vi) aralkyl,(vii) aralkoxy, (viii) alkenyl, (ix) cycloalkenyl, (x) halo-substitutedalkyl, (xi) adamantyl and (xii) thienyl, furyl, pyrrolyl, pyridyl,benzodioxolyl, imidazolyl, pyrrolidinyl, piperidinyl and indolyl; R⁴ isselected from(i) hydrogen, (ii) lower alkyl, (iii) aryl, (iv)cycloalkyl, (v) alkoxy, (vi) aralkyl, (vii) aralkoxy, (viii) alkenyl,(ix) cycloalkenyl, (x) adamantyl, (xi) halogen, (xii) halo-substitutedalkyl and (xiii) thienyl, furyl, pyrrolyl, pyridyl, benzodioxolyl,imidazolyl, pyrrolidinyl, piperidinyl and indolyl; R⁵ and R⁷ are eachindependently selected form hydrogen, lower alkyl, alkali metal salt ionand alkaline earth metal salt ion; R⁶ is hydrogen or lower alkyl; R⁸ ishydrogen or lower alkyl in the free acid form or in the form of aphysiologically acceptable and hydrolyzable ester or δ-lactone thereof,or an alkali metal salt ion or alkaline earth metal salt ion; n is 0 or1; and a is 1, 2 or 3, and wherein "aryl" by itself or as part ofanother group is a monocyclic or bicyclic aromatic group containing 6 to10 carbons in the ring portion; "alkyl" or "lower alkyl" by itself or aspart of another group contains 1 to 12 carbons; "cycloalkyl" by itselfor as part of another group contains 3 to 12 carbons; "cycloalkenyl" byitself or as part of another group contains 3 to 12 carbons.
 2. Acompound as defined in claim 1, wherein R¹ is aryl.
 3. A compound asdefined in claim 1, wherein R¹ is 4-fluorophenyl.
 4. A compound asdefined in claim 1, wherein R⁴ is hydrogen or lower alkyl.
 5. A compoundas defined in claim 1, wherein R³ is lower alkyl, aryl or cycloalkyl. 6.A compound as defined in claim 1, wherein R³ is aryl.
 7. A compound asdefined in claim 1, wherein X is trans--CH═CH--.
 8. A compound asdefined in claim 1, wherein X is cis--CH═CH--.
 9. A compound as definedin claim 1, selected from the group consisting of(3R*, 5S*,6E)-7-[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, (3R*, 5S*,6E)-7-[4-(4-Fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, (3R*, 5S*,6E)-7-[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid,(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethyl]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S,E)-4-[[2-[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid,[3S,4(E)]-4-[[2-[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[[4-(4-Fluoro-3-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl-3-hydroxybutanoicacid,(S)-4-[[[2-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-thienyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[[6-(1,3-Benzodioxol-4-yl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-5,6-diphenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-methylphenyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[[6-[[1,1'-Biphenyl]-3-yl]-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[[6-(1,3-Benzodioxol-5-yl)-4-(4-fluorophenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[[2-(1,1-Dimethylethyl)-1-(4-fluoro-3-methylphenyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[[4-(4-Fluorophenyl)-6-methyl-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, 1-oxide,(S)-4-[[[2-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-6-(2-methylphenyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, 1-oxide,(S)-4-[[[4-(4-Fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-1-pyridin-3-yl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[[4-(3,5-Dimethylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[[4-Fluorophenyl)-2-(1-methylethyl)-6-(2-pyridinyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[[4-Fluorophenyl)-6-(2-hydroxyphenyl)-2-(1-methylethyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-methylphenyl)-3-pyridinyl]ethynyl]hydroxyphosphinyl]-3-hydroxybutanoicacid, 1-oxide,(3R,5S,6E)-7-[4-(4-Fluoro-3-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid,(3R,5S,6E)-7-[4-(3,5-Dimethylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid,(3R,5S,6E)-7-[4-(4-Fluoro-2-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptanoicacid,(3R,5S,6E)-7-[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid,(3R,5S,6E)-7-[2-(4-Fluoro-methylphenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid,(3R,5S,6E)-7-[4-(4-Fluorophenyl)-2-(1-methylethyl)-5,6-diphenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid,(3R,5S,6E)-7-[2-(1,1-Dimethylethyl)-4-(4-fluorophenyl)-6-phenyl-3-pyridinyl-3,5-dihydroxy-6-heptenoicacid,(3R,5S,6E)-7-[4-Fluoro-3-methylphenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, 1-oxide,(3R,5S,6E)-7-[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-3,5-dihydroxy-6-heptenoicacid, 1-oxide,(3R,5S,6E)-7-[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-(2-methylphenyl)-3-pyridinyl-3,5-dihydroxy-6-heptenoicacid, 1-oxide,(S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]methoxy]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]methoxy]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[[4-(4-Fluorophenyl)-5-ethyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]methoxy]hydroxyphosphinyl]-3-hydroxybutanoicacid,(S)-4-[[[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethenyl)-6-phenyl-3-pyridinyl]methoxy]hydroxyphosphinyl]-3-hydroxybutanoicacid, and(S)-4-[[[4-(4-Fluorophenyl)-5-methyl-2-ethyl-6-phenyl-3-pyridinyl]methoxy]hydroxyphosphinyl]-3-hydroxybutanoicacid.
 10. A hypocholesterolemic or hypolipidemic composition comprisinga compound as defined in claim 1 and a pharmaceutically acceptablecarrier therefor.
 11. A method of inhibiting cholesterol biosynthesiswhich comprises administering to a mammal an effective amount of acompound as defined in claim
 1. 12. A compound of the formula ##STR63##or a pharmaceutically acceptable salt thereof wherein: Am is ##STR64## Xis --(CH₂)_(a) --, --CH═CH--, --C.tbd.C-- or --CH₂ O--; R¹ and R² arethe same or different and are each independently selected from(i)hydrogen, (ii) alkyl, (iii) aryl, (iv) cycloalkyl and (v) alkenyl, R³ isselected from(i) hydrogen, (ii) lower alkyl, (iii) aryl, (iv)cycloalkyl, (v) aralkyl, (vi) alkenyl, (vii) adamantyl and (vii)thienyl, furyl, pyrrolyl, pyridyl, benzodioxoyl, imidazolyl,pyrrolidinyl, piperidinyl and indolyl; R⁴ is selected from(i) hydrogen,(ii) lower alkyl, (iii) aryl, (iv) cycloalkyl, (v) aralkyl, (vi) alkenyland (vii) thienyl, furyl, pyrrolyl, pyridyl, benzodioxolyl, imidazolyl,pyrrolidinyl, piperidinyl and indolyl; R⁵ and R⁷ are each independentlyselected form hydrogen, lower alkyl, alkali metal salt ion and alkalineearth metal salt ion; R⁶ is hydrogen or lower alkyl; R⁸ is hydrogen orlower alkyl in the free acid form or in the form of a physiologicallyacceptable and hydrolyzable ester or δ-lactone thereof, or an alkalimetal salt ion or alkaline earth metal salt ion; n is 0 or 1; and a is1, 2 or 3 and wherein "aryl" by itself or as part of another group is amonocyclic or bicyclic aromatic group containing 6 to 10 carbons in thering portion; "alkyl" or "lower alkyl" by itself or as part of anothergroup contains 1 to 12 carbons; "cycloalkyl" by itself or as part ofanother group contains 3 to 12 carbons; "cycloalkenyl" by itself or aspart of another group contains 3 to 12 carbons.
 13. A compound asdefined in claim 12, wherein X is trans--CH═CH--.
 14. A compound asdefined in claim 12, wherein X is cis--CH═CH--.
 15. Ahypocholesterolemic or hypolipidemic composition comprising a compoundas defined in claim 12 and a pharmaceutically acceptable carriertherefor.
 16. A method of inhibiting cholesterol biosynthesis whichcomprises administering to a mammal an effective amount of a compound asdefined in claim
 12. 17. A compound as defined in claim 12, wherein R¹is aryl.
 18. A compound as defined in claim 12, wherein R¹ is4-fluorophenyl.
 19. A compound as defined in claim 12 wherein R⁴ ishydrogen or lower alkyl.
 20. A compound as defined in claim 12, whereinR³ is lower alkyl, aryl or cycloalkyl.
 21. A compound as defined inclaim 12, wherein R³ is aryl. 22.(S)-4-[[2-[4-(4-Fluorophenyl)-5-methyl-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]hydroxyphosphinyl]-3-hydroxybutanoicacid.